Substituted indolinones, preparation thereof and their use as pharmaceutical compositions

ABSTRACT

Indolinones of general formula I 
                         
which are inhibitors of cell proliferation, particularly of tumor cells, and inhibitors of protein kinases.

RELATED APPLICATIONS

This is a division of Ser. No. 10/002,939 filed Nov. 1, 2001, now U.S.Pat. No. 6,638,965. Benefit of U.S. Provisional Application Ser. No.60/251,055, filed on Dec. 1, 2000 is hereby claimed.

DESCRIPTION OF THE INVENTION

The present invention relates to new substituted indolinones of generalformula

the isomers, the salts thereof, particularly the physiologicallyacceptable salts thereof which have valuable properties.

The above compounds of general formula I wherein R₁ is a hydrogen atomor a prodrug group have valuable pharmacological properties,particularly an inhibiting effect on the proliferation of cultivatedhuman tumour cells, but also on the proliferation of other cells,particularly endothelial cells, e.g. in angiogenesis, on variouskinases, particularly on receptor tyrosine kinases (such as, forexample, VEGFR2, EGFR, IGF1R), non-receptor tyrosine kinases (such ase.g. c-src), and serine/threonine kinases (such as e.g. cyclin-dependentkinases), and the other compounds of the above general formula I whereinR₁ does not denote a hydrogen atom or a prodrug group, are valuableintermediate products for the preparation of the compounds mentionedabove.

The present invention thus relates to the above compounds of generalformula I, wherein

-   X denotes an oxygen or sulphur atom,-   R₁ denotes a hydrogen atom, a C₁₋₄-alkoxycarbonyl or C₂₋₄-alkanoyl    group,-   R₂ denotes a C₁₋₆-alkyl group optionally substituted by one or more    halogen atoms or a phenyl group or a C₂₋₆-alkenyl group optionally    substituted by a phenyl group, wherein the phenyl moiety may be    substituted in each case by a fluorine, chlorine, bromine or iodine    atom, by a C₁₋₃-alkyl or C₁₋₃-alkoxy group,-   a phenyl group which may be mono- or disubstituted by fluorine,    chlorine, bromine or iodine atoms, by C₁₋₃-alkyl or C₁₋₃-alkoxy    groups, wherein the substituents may be identical or different,-   a phenyl group substituted by a trifluoromethyl, carboxy,    C₁₋₃-alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or    amino group,-   a C₄₋₆-alkyl, C₃₋₇-cycloalkyl, trimethylphenyl or naphthyl group,-   a 5-membered heteroaromatic group optionally substituted by a    C₁₋₃-alkyl group, which contains, in the heteroaromatic moiety,-   an imino group optionally substituted by a C₁₋₃-alkyl group, an    oxygen or sulphur atom,-   an imino group optionally substituted by a C₁₋₃-alkyl group and an    oxygen, sulphur or nitrogen atom,-   an imino group optionally substituted by a C₁₋₃-alkyl group and two    nitrogen atoms, or an oxygen or sulphur atom and two nitrogen atoms,    and to which a phenyl ring may be fused via two adjacent carbon    atoms,-   or denotes a 6-membered heteroaromatic group optionally substituted    by a C₁₋₃-alkyl group, which contains one or two heteroatoms in the    heteroaromatic moiety and to which a phenyl ring may be fused via    two adjacent carbon atoms,-   R₃ denotes a hydrogen atom or a C₁₋₆-alkyl group,-   a phenyl group optionally substituted by a fluorine, chlorine or    bromine atom, by a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy,    C₁₋₃-alkylsulphenyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,    phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, nitro, amino,    C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₂₋₅-alkanoylamino or    N—(C₁₋₃-alkylamino)-C₂₋₅-alkanoylamino group,-   R4 denotes a phenyl or naphthyl group optionally substituted by R₇,    which may additionally be substituted by a chlorine or bromine atom    or a nitro group, a 5-membered heteroaromatic group which contains    an imino group, an oxygen or sulphur atom or an imino group, an    oxygen or sulphur atom and one or two nitrogen atoms, or-   a 6-membered heteroaromatic group which contains one, two or three    nitrogen atoms, while the abovementioned 5- and 6-membered    heteroaromatic groups may additionally be substituted by a chlorine    or bromine atom or by a methyl group or wherein a phenyl ring may be    fused to the abovementioned 5- and 6-membered heteroaromatic groups    via 2 adjacent carbon atoms, or-   R₅ and R₆ in each case independently of one another denote hydrogen    atoms or C₁₋₃-alkyl groups, and-   R₇ denotes a fluorine, chlorine, bromine or iodine atom or a cyano    group, a methoxy group or a C₂₋₃-alkoxy group, which may be    substituted in the 2 or 3 position by an amino, C₁₋₃-alkylamino,    di-(C₁₋₃-alkyl)-amino or 5- to 7-membered cycloalkyleneimino group,    while in each case an alkyl moiety in the above-mentioned alkylamino    and dialkylamino groups may additionally be substituted by a phenyl    group,-   a trifluoromethyl, nitro, amino, C₁₋₃-alkylamino,    di-(C₁₋₃-alkyl)-amino,-   C₂₋₅-alkanoylamino, N—(C₁₋₃-alkyl)-C₂₋₅-alkanoylamino,    C₁₋₅-alkylsulphonylamino, N—(C₁₋₃-alkyl)-C₁₋₅-alkylsulphonylamino,    phenylsulphonylamino, N—(C₁₋₃-alkyl)-phenylsulphonylamino,    aminosulphonyl, C₁₋₃-alkylaminosulphonyl or    di-(C₁₋₃-alkyl)-aminosulphonyl group, while in each case an alkyl    moiety in the above-mentioned alkylamino and dialkylamino groups may    additionally be substituted by a carboxy, C₁₋₃-alkoxycarbonyl,    aminocarbonyl, C₁₋₃-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)-aminocarbonyl, 2-dimethylaminoethylaminocarbonyl or    N-methyl-(2-dimethylaminoethyl)-aminocarbonyl group and in each case    the alkyl moiety of the abovementioned alkanoylamino or    alkysulphonylamino groups may additionally be substituted by a    phenyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or a 4- to    7-membered cycloalkyleneimino group,-   a C₂₋₄-alkylamino group which is terminally substituted in the 2, 3-    or 4 position by an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,    benzylamino, N—(C₁₋₃-alkyl)-benzylamino, C₂₋₅-alkanoylamino or    N—(C₁₋₃-alkyl)-C₂₋₅-alkanoylamino group and wherein additionally the    amino-hydrogen atom may be replaced by a C₂₋₅-alkanoyl, benzoyl,    C₁₋₅-alkylsulphonyl- or phenylsulphonyl group, while the    last-mentioned C₂₋₅-alkanoyl or C₁₋₅-alkylsulphonyl groups in the    alkyl moiety may be substituted by a phenyl group,-   a carbonyl group which is substituted by a hydroxy, C₁₋₃-alkoxy,    amino, C₁₋₃-alkylamino, N—(C₁₋₅-alkyl)-C₁₋₃-alkylamino or    C₅₋₇-cycloalkyleneimino group;-   a C₁₋₃-alkyl group which may be substituted by an amino,    C₁₋₅-alkylamino, C₅₋₇-cycloalkylamino or phenyl-C₁₋₃-alkylamino    group which may additionally be substituted at the amino nitrogen    atom in each case by a C₁₋₄-alkyl, C₅₋₇-cycloalkyl or C₂₋₄-alkenyl-    or C₁₋₄-alkyl group, while-   the abovementioned C₁₋₄-alkyl substituent in each case may    additionally be mono-, di- or trisubstituted by a cyano, carboxy,    C₁₋₃-alkoxycarbonyl, C₂₋₄-alkanoyl, pyridyl, imidazolyl,    benzo[1,3]dioxol or phenyl group, while the phenyl group may be    substituted by fluorine, chlorine or bromine atoms, by methyl,    methoxy, trifluoromethyl, cyano or nitro groups and the substituents    may be identical or different, or in the 2, 3 or 4 position by a    hydroxy group,-   a C₁₋₃-alkyl group which is substituted by a hydroxy, carboxy,    morpholino, thiomorpholino, 1-oxo-thiomorpholino,    1,1-dioxo-thiomorpholino, piperazino, N—(C₁₋₃-alkyl)-piperazino or    N-benzyl-piperazino group, by a 5- to 7-membered    cycloalkenyleneimino group or by a 4- to 7-membered    cycloalkyleneimino group, while the abovementioned 5- to 7-membered    cycloalkyleneimino groups may be substituted by one or two    C₁₋₃-alkyl groups, which may in turn be terminally substituted by a    hydroxy, amino or C₂₋₄-alkanoylamino group, or by a C₅₋₇-cycloalkyl    or phenyl group and by a hydroxy group and in the abovementioned    cycloalkyleneimino groups a methylene group adjacent to the nitrogen    atom may be replaced by a carbonyl group,-   a C₁₋₃-alkyl group which is substituted by a 5- to 7-membered    cycloalkyleneimino group, while a phenyl group optionally mono- or    disubstituted by fluorine, chlorine or bromine atoms or by methyl or    methoxy groups, wherein the substituents may be identical or    different, or an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or    pyrimidino group optionally substituted by a fluorine, chlorine,    bromine or iodine atom, by a methyl, methoxy or amino group is fused    to the abovementioned 5- to 7-membered cycloalkyleneimino groups via    2 adjacent carbon atoms, while the above-mentioned monosubstituted    phenyl groups may additionally be substituted by a fluorine,    chlorine or bromine atom, by a methyl, methoxy or nitro group, or-   denotes an imidazolyl or 1H-C₁₋₃-alkylimidazolyl group.

If R₁ denotes a hydrogen atom, the present invention also relates to thetautomeric compounds of formula I′

The invention also relates to compounds of formula I, wherein R₁ denotesa cleavable prodrug group.

The invention further relates to pharmaceutical compositions containingthe pharmacologically active compound, their use and processes forpreparing them.

Preferred compounds of formula I are those wherein the sulphonylaminogroup of formula R₂—SO₂NR₆— is linked to the 5-position of theindolinone group.

Preferred compounds of formula I are those wherein

R₇ denotes a C₁₋₃-alkyl group which is substituted by a hydroxy,carboxy, morpholino, thiomorpholino, 1-oxo-thiomorpholino,1,1-dioxo-thiomorpholino, piperazino, N—(C₁₋₃-alkyl)-piperazino orN-benzyl-piperazino group, by a 5- to 7-membered cycloalkenyleneiminogroup or by a 4- to 7-membered cycloalkyleneimino group, while theabovementioned 5- to 7-membered cycloalkyleneimino groups may besubstituted by one or two C₁₋₃-alkyl groups, which may in turn beterminally substituted by an amino or C₂₋₄-alkanoylamino group, or by aC₅₋₇-cycloalkyl or phenyl group and by a hydroxy group and in theabovementioned cycloalkyleneimino groups a methylene group adjacent tothe nitrogen atom may be replaced by a carbonyl group.

Also preferred are compounds of formula I wherein

R₃ denotes a phenyl group optionally substituted by a fluorine, chlorineor bromine atom, by a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy,C₁₋₃-alkylsulphenyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, nitro, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₂₋₅-alkanoylamino orN—(C₁₋₃-alkylamino)-C₂₋₅-alkanoylamino group, more particularly a phenylgroup optionally substituted by an fluorine, chlorine, bromine or iodineatom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro or amino group.

In another preferred embodiment R₂ denotes a C₁₋₄-alkyl group optionallysubstituted by one or more halogen atoms or a phenyl group, aC₃₋₅-cycloalkyl group or a C₂₋₄-alkenyl group optionally substituted bya phenyl group, wherein the phenyl moiety in each case may besubstituted by a fluorine, chlorine, bromine or iodine atom or by aC₁₋₃-alkyl or C₁₋₃-alkoxy.

Moreover, the carboxy, amino or imino groups present in a compound ofthe above general formula I may be substituted by groups which can becleaved in vivo.

In addition to the alkoxycarbonyl and alkanoyl groups already mentionedhereinbefore, groups which can be cleaved in vivo may also be included,such as an acyl group such as the benzoyl, pyridinoyl, pentanoyl orhexanoyl group, an allyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl groupsuch as the tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl,octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, aphenyl-C₁₋₆-alkoxycarbonyl group such as the benzyloxycarbonyl,phenylethoxycarbonyl or phenylpropoxycarbonyl group, aC₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl orR_(c)CO—O—(R_(d)CR_(e))—O—CO-group, wherein

-   R_(c) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl- or    phenyl-C₁₋₃-alkyl group,-   R_(e) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or    phenyl group and-   R_(d) denotes a hydrogen atom or a C₁₋₃-alkyl group or a    R_(f)CO—O—(R_(g)CR_(h))—O-Rest wherein-   R_(f) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or    phenyl-C₁₋₃-alkyl group,-   R_(g) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or    phenyl group and-   R_(h) denotes a hydrogen atom or a C₁₋₃-alkyl group,    while the abovementioned ester groups may also be used as a group    which can be converted in vivo into a carboxy group.

Preferred compounds of the above general formula I are those wherein

-   X denotes an oxygen atom,-   R₁ denotes a hydrogen atom,-   R₂ denotes a C₁₋₃-alkyl group optionally substituted by one or more    fluorine atoms or a phenyl group or a C₂₋₄-alkenyl group optionally    substituted by a phenyl group;-   a phenyl group which may be mono- or disubstituted by fluorine,    chlorine, bromine or iodine atoms, by C₁₋₃-alkyl or C₁₋₃-alkoxy    groups, wherein the substituents may be identical or different,-   a phenyl group substituted by a trifluoromethyl, carboxy,    C₁₋₃-alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or    amino group,-   a C₄₋₆-alkyl, C₃₋₇-cycloalkyl, trimethylphenyl or naphthyl group, or-   a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl    or 1-(C₁₋₃-alkyl)-imidazolyl group optionally substituted by a    C₁₋₃-alkyl group,-   R₃ denotes a hydrogen atom or a C₁₋₄-alkyl group, or-   a phenyl group optionally substituted by a fluorine, chlorine,    bromine or iodine atom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro or amino    group,-   R₄ denotes a phenyl group optionally substituted by R₇, which may    additionally be substituted by a chloro or nitro group,-   R₅ and R₆ in each case denote a hydrogen atom, and-   R₇ denotes a fluorine, chlorine, bromine or iodine atom,-   a methoxy, nitro, cyano, carboxy, C₁₋₃-alkoxycarbonyl,    aminocarbonyl, C₁₋₃-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylaminocarbonyl,    N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl or 5- to 7-membered    cycloalkyleneiminocarbonyl group,-   a C₁₋₃-alkyl group which is substituted by a carboxy,    C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylaminocarbonyl,    N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl, 5- to 7-membered    cycloalkyleneiminocarbonyl, amino, C₁₋₃-alkylamino,    di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkylamino,    N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylamino or 5- to 7-membered    cycloalkyleneimino group,-   while the abovementioned 5- to 7-membered cycloalkyleneimino group    may be substituted by one or two C₁₋₃-alkyl groups, which may in    turn be terminally substituted by a hydroxy, amino or    C₂₋₄-alkanoylamino group, and at the same time in the abovementioned    5- to 7-membered cycloalkyleneimino moieties a methylene group in    the 2 position may be replaced by a carbonyl group or in the    abovementioned 6- and 7-membered cycloalkyleneimino moieties a    methylene group in the 4 position may be replaced by an oxygen atom,    by an imino, N—(C₁₋₃-alkyl)-imino, N-(phenyl-C₁₋₃-alkyl)-imino or    N—(C₁₋₅-alkoxycarbonyl)-imino group,-   an amino, C₁₋₃-alkylamino, phenyl-C₁₋₃-alkylamino,    C₁₋₅-alkanoylamino, phenyl-C₁₋₄-alkanoylamino,    C₁₋₅-alkoxycarbonylamino, phenyl-C₁₋₃-alkoxycarbonylamino,    C₁₋₅-alkylsulphonylamino, phenyl-C₁₋₃-alkylsulphonylamino- or    phenylsulphonylamino group, wherein the hydrogen atom of the amino    group may be replaced by a C₁₋₃-alkyl group, while the C₁₋₃-alkyl    moiety may be substituted by a carboxy, C₁₋₃-alkoxycarbonyl,    aminocarbonyl, C₁₋₃-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylaminocarbonyl,    N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl,    2-dimethylaminoethylaminocarbonyl,    N-methyl-(2-dimethylaminoethyl)-aminocarbonyl- or    C₄₋₆-cycoalkylenimnocarbonyl group or from position 2 by an amino,    C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkylamino,    N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylamino, C₂₋₅-alkanoylamino,    N—(C₁₋₃-alkyl)-C₂₋₅-alkanoylamino, C₁₋₅-alkoxycarbonylamino- or    N—(C₁₋₅-alkoxycarbonyl)-C₁₋₃-alkylamino group,-   imidazolyl or 1-C₁₋₃-alkylimidazolyl group.

Particularly preferred compounds of formula I are those wherein

-   R₇ denotes a C₁₋₃-alkyl group which is substituted by a carboxy,    C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylaminocarbonyl,    N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl, 5- to 7-membered    cycloalkyleneiminocarbonyl, amino, C₁₋₃-alkylamino,    di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkylamino,    N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylamino- or 5- to 7-membered    cycloalkyleneimino group,-   while the abovementioned 5- to 7-membered cycloalkyleneimino group    may be substituted by one or two C₁₋₃-alkyl groups, which may in    turn be terminally substituted by an amino or C₂₋₄-alkanoylamino    group, and at the same time in the abovementioned 5- to 7-membered    cycloalkyleneimino moieties a methylene group may be replaced in the    2 position by a carbonyl group or in the abovementioned 6- and    7-membered cycloalkyleneimino moieties a methylene group in the 4    position may be replaced by an oxygen atom, by an imino,    N—(C₁₋₃-alkyl)-imino, N-(phenyl-C₁₋₃-alkyl)-imino or    N—(C₁₋₅-alkoxycarbonyl)-imino group.

Particularly preferred compounds of general formula I are those wherein

-   X denotes an oxygen atom,-   R₁ denotes a hydrogen atom,-   R₂ denotes a C₁₋₃-alkyl group optionally substituted by a phenyl    group, a C₁₋₃-perfluoroalkyl group or a phenylvinyl group,-   a phenyl group which may be substituted by a fluorine, chlorine,    bromine or iodine atom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro, amino,    cyano or aminomethyl group,-   a C₄₋₆-alkyl, C₃₋₇-cycloalkyl, trimethylphenyl or naphthyl group,-   a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl    or 1-(C₁₋₃-alkyl)-imidazolyl group optionally substituted by a    C₁₋₃-alkyl group,-   R₃ denotes a phenyl group optionally substituted by a fluorine,    chlorine, bromine or iodine atom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy,    nitro or amino group,-   R₄ denotes a phenyl group which may be substituted by R₇ and    additionally by a chlorine atom or a nitro group, while-   R₇ denotes a fluorine, chlorine, bromine or iodine atom,-   a methoxy, nitro, cyano, carboxy, methoxycarbonyl, aminocarbonyl,    methylaminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl,    N-benzylmethylaminocarbonyl, pyrrolidinocarbonyl or    piperidinocarbonyl group,-   a methyl or ethyl group which may be substituted by a carboxy,    methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,    dimethylaminocarbonyl, benzylaminocarbonyl,    N-benzyl-methylaminocarbonyl, pyrrolidinocarbonyl,    piperidinocarbonyl, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino,    benzylamino, N-benzyl-C₁₋₄-alkylamino, C₂₋₄-alkanoylamino,    N—C₁₋₄-alkyl-C₂₋₄-alkanoylamino, tert.butyloxycarbonylamino,    N-methyl-tert.butyloxycarbonylamino, pyrrolidino, pyrrolidinomethyl,    hydroxypyrrolidinomethyl, hydroxymethylpyrrolidinomethyl,    piperidino, 4-(3-aminopropyl)-piperidino,    4-(3-acetylaminopropyl)-piperidino, dimethylpiperidino,    2-oxo-piperidino, piperazino, 4-methyl-piperazino,    4-benzyl-piperazino, 4-tert.butoxycarbonylpiperazino or morpholino    group, or-   an amino, methylamino, ethylamino, C₁₋₃-alkanoylamino,    phenylacetylamino, tert.butoxycarbonylamino,    piperidinomethylcarbonylamino, C₁₋₄-alkylsulphonylamino,    phenyl-methylsulphonylamino or phenylsulphonylamino group, wherein    the hydrogen atom of the amino group may be replaced by a methyl,    ethyl or propyl group, while the methyl or ethyl moiety in each case    may be substituted by a carboxy, methoxycarbonyl, aminocarbonyl,    methylaminocarbonyl, dimethylaminocarbonyl,-   2-dimethylaminoethylaminocarbonyl or    N-methyl-(2-dimethylaminoethyl)-aminocarbonyl group or the ethyl    moiety may also be substituted from position 2 by an amino,    methylamino, dimethylamino, benzylalkylamino, N-benzyl-methylamino,    C₂₋₃-alkanoylamino, N-methyl-C₂₋₃-alkanoylamino,    tert.butyloxycarbonylamino or N-methyl-tert.butyloxycarbonylamino    group,-   an imidazolyl or 1-methylimidazolyl group,-   R₅ and R₆ in each case denote a hydrogen atom,-   and the isomers and the salts thereof.

Particularly preferred are compounds of formula I wherein R₄ denotes aphenyl group substituted by R₇ in the 3 or 4 position, particularly inthe 4 position.

According to the invention, the new compounds are obtained, for example,by the following methods known in principle from the literature:

-   a. reacting a compound of general formula

wherein

-   X, R₂, R₃ and R₆ are as hereinbefore defined and-   R₈ has one of the meanings given for R₁ or may denote a protecting    group for the nitrogen atom of the lactam group, while R₈ may also    represent a bond to a solid phase optionally formed via a spacer,    and-   Z₁ denotes a halogen atom, a hydroxy, alkoxy or aralkoxy group, e.g.    a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,-   with an amine of general formula

wherein

-   R₄ and R₅ are as hereinbefore defined,    and if necessary subsequently cleaving any protecting group used for    the nitrogen atom of the lactam group or from a solid phase.

The protecting group used for the nitrogen atom of the lactam group maybe, for example, an acetyl, benzoyl, ethoxycarbonyl,tert.butyloxycarbonyl or benzyloxycarbonyl group and

the solid phase used may be a resin such as a4-(2′,4′-dimethoxyphenylaminomethyl)-phenoxy resin, while the bond mayexpediently be effected via the amino group, or a p-benzyloxybenzylalcohol resin, while the bond may expediently be effected via anintermediate member such as a 2,5-dimethoxy-4-hydroxy-benzyl derivative.

The reaction is conveniently carried out in a solvent such asdimethylformamide, toluene, acetonitrile, tetrahydrofuran,dimethylsulphoxide, dichloromethane or mixtures thereof, optionally inthe presence of an inert base such as triethylamine,N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperaturesbetween 20 and 175° C., while any protecting group used maysimultaneously be cleaved by transamidation.

If Z₁ in a compound of general formula II denotes a halogen atom, thereaction is preferably carried out in the presence of an inert base attemperatures between 20 and 120° C.

If Z₁ in a compound of general formula II denotes a hydroxy, alkoxy oraralkoxy group, the reaction is preferably carried out at temperaturesbetween 20 and 200° C.

If any protecting group used subsequently has to be cleaved, this isconveniently carried out either hydrolytically in an aqueous oralcoholic solvent, e.g. in methanol/water, ethanol/water,isopropanol/water, tetrahydrofuran/water, dioxane/water,dimethylformamide/water, methanol or ethanol in the presence of analkali metal base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide at temperatures between 0 and 100° C., preferably attemperatures between 10 and 50° C.,

or advantageously by transamidation with an organic base such asammonia, methylamine, butylamine, dimethylamine or piperidine in asolvent such as methanol, ethanol, dimethylformamide and mixturesthereof or in an excess of the amine used at temperatures between 0 and100° C., preferably at temperatures between 10 and 50° C.

Any solid phase used is preferably cleaved using trifluoroacetic acidand water at temperatures between 0 and 35° C., preferably at ambienttemperature.

-   b. reacting a compound of general formula

wherein

-   R₁ and R₃ to R₆ are as hereinbefore defined, with a compound of    general formula    R₂—SO₂—OH  (V),    wherein-   R₂ is as hereinbefore defined, or with the reactive derivatives    thereof.

The reaction is preferably carried out in a solvent such asdichloromethane, diethylether, tetrahydrofuran, toluene, dioxane,acetonitrile, dimethylsulphoxide or dimethylformamide, optionally with areactive derivative of a compound of general formula V such as thehalide thereof, in the presence of an inorganic or tertiary organicbase, preferably at temperatures between 0° C. and the boilingtemperature of the solvent used, preferably at temperatures between 50and 100° C.

With a corresponding sulphonic acid the reaction is preferably carriedout in the presence of a dehydrating agent, e.g. in the presence ofisobutyl chloroformate, tetraethyl orthocarbonate, trimethylorthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphoruspentoxide, N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N′-dicyclohexylcarbodiimide/1-hydroxy-benztriazole,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole,N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, andoptionally with the addition of a base such as pyridine,4-dimethylaminopyridine, N-methyl-morpholine or triethylamine,expediently at temperatures between 0 and 150° C., preferably attemperatures between 0 and 100° C.

If according to the invention a compound of general formula I isobtained which contains an alkoxycarbonyl group, this can be convertedby hydrolysis into a corresponding carboxy compound, or

-   if a compound of general formula I is obtained which contains an    amino or alkylamino group, this may be converted by reductive    alkylation into a corresponding alkylamino or dialkylamino compound,    or-   if a compound of general formula I is obtained which contains an    amino or alkylamino group, this may be converted by acylation into a    corresponding acyl compound, or-   if a compound of general formula I is obtained which contains a    carboxy group, this may be converted by esterification or amidation    into a corresponding ester or aminocarbonyl compound, or-   if a compound of general formula I is obtained which contains a    nitro group, this can be converted by reduction into a corresponding    amino compound, or-   if a compound of general formula I is obtained which contains a    cyano group, this can be converted by reduction into a corresponding    aminomethyl compound.

The subsequent hydrolysis is preferably carried out in an aqueoussolvent, e.g. in water, isopropanol/water, tetrahydrofuran/water ordioxane/water, in the presence of an acid such as trifluoroacetic acid,hydrochloric acid or sulphuric acid or in the presence of an alkalimetal base such as lithium hydroxide, sodium hydroxide or potassiumhydroxide at temperatures between 0 and 100° C., preferably attemperatures between 10 and 50° C.

The subsequent reductive alkylation is preferably carried out in asuitable solvent such as methanol, methanol/water,methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane ordimethylformamide, optionally with the addition of an acid such ashydrochloric acid in the presence of catalytically activated hydrogen,e.g. hydrogen in the presence of Raney nickel, platinum orpalladium/charcoal, or in the presence of a metal hydride such as sodiumborohydride, sodium cyanoborohydride, lithium borohydride or lithiumaluminium hydride at temperatures between 0 and 100° C., preferably attemperatures between 20 and 80° C.

The subsequent acylation is preferably carried out in a solvent such asmethylene chloride, diethylether, tetrahydrofuran, toluene, dioxane,acetonitrile, dimethylsulphoxide or dimethylformamide, optionally in thepresence of an inorganic or a tertiary organic base, preferably attemperatures between 20° C. and the boiling temperature of the solventused. The acylation with a corresponding acid is preferably carried outin the presence of a dehydrating agent, e.g. in the presence of isobutylchloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate,2,2-dimethoxypropane, tetramethoxysilane, thionylchloride,trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexyl-carbodiimide/N-hydroxysuccinimide,N,N′-dicyclohexylcarbodiimide/1-hydroxy-benztriazole,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole,N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, andoptionally with the addition of a base such as pyridine,4-dimethylamino-pyridine, N-methyl-morpholine or triethylamine,conveniently at temperatures between 0 and 150° C., preferably attemperatures between 0 and 100° C., and the acylation with acorresponding reactive compound such as an anhydride, ester, imidazolideor halide thereof is optionally carried out in the presence of atertiary organic base such as triethylamine, N-ethyl-diisopropylamine orN-methyl-morpholine at temperatures between 0 and 150° C., preferably attemperatures between 50 and 100° C.

The subsequent esterification or amidation is expediently carried out byreacting a corresponding reactive carboxylic acid derivative with acorresponding alcohol or amine as described hereinbefore.

The subsequent reduction of a nitro group is preferably carried out byhydrogenolysis, e.g. with hydrogen in the presence of a catalyst such aspalladium/charcoal or Raney nickel in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid or glacial acetic acid at temperatures of between 0and 50° C., but preferably at ambient temperature, and at a hydrogenpressure of 1 to 7 bar, but preferably 3 to 5 bar.

The subsequent reduction of a cyano group is preferably carried out byhydrogenolysis, e.g. with hydrogen in the presence of a catalyst such aspalladium/charcoal or Raney nickel in a solvent such as methanolicammonia, ethanolic ammonia, ethyl acetate, dimethylformamide,dimethylformamide/acetone, dichloromethane or glacial acetic acid,optionally with the addition of an acid such as hydrochloric acid orglacial acetic acid at temperatures of between 0 and 50° C., butpreferably at ambient temperature, and at a hydrogen pressure of 1 to 7bar, but preferably 3 to 5 bar.

In the reactions described hereinbefore, any reactive groups presentsuch as carboxy, amino, alkylamino or imino groups may be protectedduring the reaction by conventional protecting groups which are cleavedagain after the reaction.

For example, a protecting group for a carboxyl group may be atrimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranylgroup and

protecting groups for an amino, alkylamino or imino group may be anacetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groupand additionally, for the amino group, a phthalyl group.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide, at temperatures between 0 and 100° C.,preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid or glacial acetic acid at temperatures between 0 and50° C., but preferably at ambient temperature, and at a hydrogenpressure of 1 to 7 bar, but preferably 3 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesof between 0 and 50° C., but preferably at ambient temperature.

A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisol.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxane, ethylacetate or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20 and 50° C.

Moreover, chiral compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers.

Thus, for example, the compounds of general formula I obtained whichoccur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes and compounds ofgeneral formula I with at least 2 asymmetric carbon atoms may beresolved into their diastereomers on the basis of theirphysical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid,aspartic acid, N-acetylaspartic acid or quinic acid. An optically activealcohol may be for example (+)- or (−)-menthol and an optically activeacyl group in amides, for example, may be a (+)- or(−)-menthyloxycarbonyl group.

Furthermore, the compounds of formula I obtained may be converted intothe salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid, maleic acid ormethanesulphonic acid.

Moreover, if the new compounds of formula I thus obtained contain acarboxy group, they may subsequently, if desired, be converted into thesalts thereof with inorganic or organic bases, particularly forpharmaceutical use into the physiologically acceptable salts thereof.Suitable bases for this purpose include for example sodium hydroxide,potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

The compounds of general formulae II to V used as starting materials areknown from the literature in some cases or may be obtained by methodsknown from the literature or are described in the Examples. For example,the compounds of general formula IV are described in German PatentApplication 198 24 922.5 of 4^(th) Jun. 1998.

As already mentioned hereinbefore, the new compounds of general formulaI wherein R₁ denotes a hydrogen atom or a prodrug group have valuablepharmacological properties, particularly an inhibiting effect on theproliferation of cultivated human cells, especially tumour cells, butalso on the proliferation of other cells, particularly endothelialcells, e.g. in angiogenesis.

For example, the compounds listed in Table 1 were tested for theirbiological properties as follows:

Test 1

Inhibition of the Proliferation of Cultivated Human Tumour Cells

Cells of the Leiomyosarcoma tumour cell line SK-UT-1B or non-small-celllung tumour cell line NCI-H460 (obtained from the American Type CultureCollection (ATCC)) were cultivated in Minimum Essential Medium withnon-essential amino acids (Gibco), supplemented with sodium pyruvate (1mMol), glutamine (2 mMol) and 10% foetal calf serum (Gibco) or RPMI1640Medium (Gibco) and 10% foetal calf serum (Gibco) and harvested in thelogarithmic growth phase. Then the SK-UT-1B cells were placed inCytostar® multi-well plates (Amersham) at a density of 4000 cells perwell or 3000 cells per well for NCI-H460 cells and incubated overnightin an incubator. Various concentrations of the compounds (dissolved inDMSO; final concentration: 0.1%) were added to the cells. After 48hours' incubation, ¹⁴C-thymidine (Amersham) was added to each well andincubation was continued for a further 24 hours. The quantity of¹⁴C-thymidine which was incorporated into the tumour cells in thepresence of the inhibitor and which represents the number of cells inthe S phase was measured in a Wallace 1450 Microbeta LiquidScintillation Counter. IC₅₀ values for the inhibition of theproliferation (=inhibition of incorporated ¹⁴C-thymidine) werecalculated, correcting for the background radiation. All themeasurements were done twice.

Test 2

In Vivo Effects on Tumour-bearing Nude Mice

10⁶ cells [SK-UT-1B, or non-small cell lung tumour NCI-H460 (obtainedfrom ATCC)] in a volume of 0.1 ml were injected subcutaneously into maleand/or female nude mice (NMRI nu/nu; 25–35 g; N=10–20); alternatively,small fragments of SK-UT-1B or NCI-H460 cell clumps were implantedsubcutaneously. One to three weeks after injection or implantation aninhibitor was administered orally (by oesophageal tube) daily for aperiod of 2 to 4 weeks. The tumour size was measured three times a weekusing a digital sliding gauge. The effect of a compound on the tumourgrowth was determined as a percentage inhibition compared with a controlgroup treated with placebo.

The following Table contains the results obtained with the in vitro Test1 (++ denotes <0.01 μM, + denotes 0.01–1.0 μM): Compound Inhibition ofSKUT-1B (Example No.) proliferation 2 + 4 ++ 9 + 12 + 20 + 22 + 23 + 31++ 36 ++ 42 + 56 ++ 58 + 66 ++ 70 + 71 + 72 + 80 ++ 88 + 98 + 99 ++ 101++ 104 ++ 112 ++ 117 + 120 ++ 134 ++ 142 + 143 + 144 + 145 + 158 + 164 +186 ++ 207 +

In view of their biological properties, the new compounds of generalformula I, their isomers and their physiologically acceptable salts aresuitable for treating conditions characterised by excessive or anomalouscell proliferation.

Such diseases include (without any claim to completeness): viralinfections (e.g. HIV and Kaposi's sarcoma); inflammation and autoimmunediseases (e.g. colitis, arthritis, Alzheimer's disease,glomerulonephritis and wound healing); bacterial, fungal and/orparasitic infection; leukaemias, lymphoma and solid tumours; skindiseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g.restenosis and hypertrophy).

The new compounds may be used for the short-term or long-term treatmentof the abovementioned conditions, possibly in conjunction with otherstate-of-the-art compounds such as other cytostatics.

The dosage required to achieve the desired effect is expediently from0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg, by intravenous route and0.1 to 100 mg/kg, preferably 0.3 to 30 mg/kg by oral route, in each case1 to 4 times a day. For this purpose, the compounds of formula Iprepared according to the invention, optionally combined with otheractive substances, may be formulated with one or more inert conventionalcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethyleneglycol, propyleneglycol,cetylstearylalcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, to produce conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories or as solutions for injections orinfusions.

The Examples which follow are intended to illustrate the inventionwithout restricting it:

Abbreviations Used:

CDI N,N'-carbonyldiimidazole DMF dimethylformamide DMSOdimethylsulphoxide TBTUO-(benzotriazol-1-yl)-N,N,N'-N'-bis(tetramethylene)-uroniumhexafluorophosphate THF tetrahydrofuran

Preparation of the Starting Compounds:

EXAMPLE I 4-[N-Acetyl-N-(2-trifluoracetylaminoethyl)-amino]-aniline a.4-(2-tert.Butoxycarbonylamino-ethylamino)-nitrobenzene

4.2 g (29.7 mmol) of N-tert.butoxycarbonyl-ethylenediamine, 5.0 g (31.2mmol) of 4-fluoro-nitrobenzene and 7.0 g (50.6 mmol) of potassiumcarbonate are stirred in 25 ml of DMSO for 9 hours at 60° C. Aftercooling the mixture is diluted with water and extracted with ethylacetate. The combined organic extracts are dried and evaporated down.The residue is stirred with petroleum ether, decanted off and evaporateddown again. The product is stirred with ether and suction filtered.

Yield: 3.2 g (38% of theory),

Melting point: 119° C.

R_(f) value: 0.5 (silica gel; toluene/ethyl acetate=7:3)

C₁₃H₁₉N₃O₄ (281.31)

Mass spectrum: (M−H)⁻32 280

b. 4-(2-trifluoroacetylamino-ethylamino)-nitrobenzene

1.5 g (5.3 mmol) of4-(2-tert.butoxycarbonylamino-ethylamino)-nitrobenzene are stirred in 15ml of trifluoroacetic acid for 3 hours at ambient temperature. Then 0.8ml (5.7 mmol) of trifluoroacetic acid anhydride are added while coolingwith ice. The reaction is left overnight to come up to ambienttemperature. It is then evaporated down, diluted with water and madealkaline with sodium hydrogen carbonate. The crude product is suctionfiltered and purified by chromatography (silica gel;dichloromethane/methanol=98:2).

Yield: 1.2 g (81% of theory),

R_(f) value: 0.5 (silica gel; dichloromethane/methanol=19:1)

C₁₀H₁₀F₃N₃O₃ (277.21)

Mass spectrum: (M−H)⁻=276

c. 4-[N-Acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-nitrobenzene

0.6 g (2.1 mmol) of 4-(2-trifluoroacetylamino-ethylamino)-nitrobenzeneare dissolved in 10 ml of glacial acetic acid and after the addition of2 ml (21.2 mmol) of acetic acid anhydride stirred for 5 hours at 80° C.and overnight at ambient temperature. The solvent is distilled off, theresidue is made alkaline with sodium hydrogen carbonate and extractedwith ethyl acetate. The combined organic extracts are dried andevaporated down.

Yield: 0.7 g (97% of theory),

R_(f) value: 0.4 (silica gel; dichloromethane/methanol=19:1)

C₁₂H₁₂F₃N₃O₄ (319.24)

Mass spectrum: (M−H)⁻=318

d. 4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-aniline

0.7 g (2.1 mmol) of4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-nitrobenzene aredissolved in 20 ml of methanol and after the addition of 100 mg of 10%palladium on activated charcoal hydrogenated with hydrogen for 3 hours.Then the catalyst is filtered off and evaporated down.

Yield: 0.6 g (91% of theory),

R_(f) value: 0.7 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₂H₁₄F₃N₃O₂ (289.26)

Mass spectrum: (M−H)⁻=288, (M+Na)⁺=312

The following compounds were prepared analogously to Example I:

(1) 4-[N-(2-dimethylamino-ethyl)-N-acetyl-amino]-aniline

R_(f) value: 0.3 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₂H₁₉N₃O (221.31)

Mass spectrum: (M+H)⁺=222

(2) 4-[N-(2-acetylamino-ethyl)-N-acetyl-amino]-aniline

R_(f) value: 0.4 (silica gel; ethyl acetate/methanol=8:2)

C₁₂H₁₇N₃O₂ (235.28)

Mass spectrum: (M+Na)⁺=258, (M−H)⁻=234

(3) 4-[N-(2-acetylamino-ethyl)-N-propionyl-amino]-aniline

R_(f) value: 0.4 (silica gel; ethyl acetate/methanol=9:1)

(4) [N-(2-propionylamino-ethyl)-N-propionyl-amino]-aniline

R_(f) value: 0.5 (silica gel; ethyl acetate/methanol=9:1)

(5) 4-{N-[2-(N-acetyl-N-methyl-amino)-ethyl]-N-propionyl-amino}-aniline

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/ammonia=19:1:0.1)

C₁₄H₂₁N₃O₂ (263.34)

Mass spectrum: (M+Na)⁺=286

(6) 4-{N-[2-(N-acetyl-N-methyl-amino)-ethyl]-N-acetyl-amino}-aniline

R_(f) value: 0.3 (silica gel; ethyl acetate/methanol=9:1)

C₁₃H₁₉N₃O₂ (249.31)

Mass spectrum: (M−H)⁻=248, (M+Na)⁺=272

(7) 4-(dimethylaminocarbonylmethylamino)-aniline

R_(f) value: 0.6 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₂H₁₅N₃O (193.25)

Mass spectrum: (M+H)⁺=194, (M+Na)⁺=216

(8) 4-(N-ethoxycarbonylmethyl-N-acetyl-amino)-aniline

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₂H₁₆N₂O₃ (236.27)

Mass spectrum: (M−H)⁻=235, (M+Na)⁺=259

(9) 4-[N-(3-dimethylamino-propyl)-N-propionyl-amino]-aniline

R_(f) value: 0.2 (silica gel;dichloromethane/methanol/ammonia=8.5:1.5:0.15)

C₁₄H₂₃N₃O (249.36)

Mass spectrum: (M−H)⁻=248, (M+H)⁺=250

EXAMPLE II 4-[N-(2-benzyloxycarbonylamino-ethyl)-N-acetyl-amino)-aniline

450 mg (1.26 mmol) of4-[N-(2-benzyloxycarbonylamino-ethyl)-N-acetyl-amino)-nitrobenzene(prepared analogously to Example I) are dissolved in 20 ml of methanoland after the addition of 100 mg of Lindlar catalyst hydrogenated for 2hours with hydrogen. The catalyst is filtered off, the solution isevaporated down.

Yield: 410 mg (99% of theory),

R_(f) value: 0.4 (silica gel; ethyl acetate/dichloromethane=7:3)

C₁₈H₂₁N₃O₃ (327.38)

Mass spectrum: (M+Na)⁺=350, (M−H)⁻=326

The following compounds were prepared analogously to Example II:

(1) 4-{N-[2-(N-benzyl-N-methyl-amino)-ethyl]-N-acetyl-amino}-aniline

R_(f) value: 0.7 (silica gel; ethyl acetate/methanol/ammonia=9:1:0.1)

C₁₈H₂₃N₃O (297.40)

Mass spectrum: (M+H)⁺=298, (M−H)⁻=296

(2) 4-{N-[2-(N-benzyl-N-methyl-amino)-ethyl]-N-propionyl-amino}-aniline

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₉H₂₅N₃O (311.43)

Mass spectrum: (M+H)⁺=312

EXAMPLE III4-[N-(2-trifluoroacetylamino-ethyl)-N-methylsulphonyl-amino]-aniline a.4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene

20 g (92.5 mmol) of 4-(methylsulphonylamino)-nitroaniline are dissolvedin 155 ml of DMSO and while cooling with ice 11.7 (104 mmol) ofpotassium tert. butoxide are added. After 1 hour 13.5 ml (121 mmol) ofethyl bromoacetate are added. The mixture is stirred for 18 hours atambient temperature and the reaction solution is then poured onto icewater. It is extracted with ethyl acetate. The organic phase is washedwith water, dried and freed from the solvent in vacuo. The residue istriturated with petroleum ether.

Yield: 27.1 g (97% of theory),

Melting point: 73–75° C.

R_(f) value: 0.8 (silica gel; dichloromethane/ethyl acetate=9:1)

C₁₁H₁₄N₂O₆S (302.31)

Mass spectrum: (M+Na)⁺=325, (M−H)⁻=301

b. 4-(N-carboxymethyl-N-methylsulphonyl-amino)-nitrobenzene

26.8 g (88.6 mmol) of4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene aresuspended in 320 ml of ethanol and combined with 268 ml of 1 N sodiumhydroxide solution. The mixture is stirred for one hour at ambienttemperature and then 268 ml of 1 N hydrochloric acid are added. Theprecipitate formed is suction filtered, washed with a little ethanol andether, and dried in vacuo.

Yield: 21.9 g (90% of theory),

Melting point: 215–218° C.

R_(f) value: 0.6 (silica gel; dichloromethane/methanol/glacial aceticacid=9:1:0.1)

C₉H₁₀N₂O₆S (274.25)

Mass spectrum: (M−H)⁻=273

c. 4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene

2.5 g (15.4 mmol) of CDI are added to a solution of 3 g (10.9 mmol) of4-(N-carboxymethyl-N-methylsulphonyl-amino)-nitrobenzene in 30 ml ofDMF. The mixture is stirred for one hour at ambient temperature. ThenNH₃ is piped in at 0° C. over a period of 10 min. After 2 hours'stirring at ambient temperature 100 ml of water are added. The mixtureis extracted with ethyl acetate, the organic phase is washed with water,dried over magnesium sulphate and evaporated to dryness. The residue isstirred with water, suction filtered and washed with ether.

Yield: 2.3 g (78% of theory),

Melting point: 160° C.

R_(f) value: 0.5 (silica gel; ethyl acetate/dichloromethane=3:2)

d. 4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-nitrobenzene

2.3 g (8.4 mmol) of4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene arerefluxed in 35 ml (35 mmol) of borane-THF (1 M solution in THF) 7 hours.Then 30 ml of 6 N hydrochloric acid are added, and the mixture isrefluxed for another 8 hours. The solvent is distilled off, the residueis mixed with water and extracted with ethyl acetate. The aqueous phaseis made alkaline with potassium carbonate and extracted withdichloromethane. The organic phase is separated off, dried andevaporated down.

Yield: 1.7 g (77% of theory),

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₉H₁₃N₃O₄S (259.29)

Mass spectrum: (M+H)⁺=260, (M−H)⁻=258

e. 4-[N-(2-trifluoroacetylamino-ethyl)-N-methylsulphonyl-amino]-aniline

Prepared analogously to Example Ib by reacting4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-nitrobenzene withtrifluoroacetic acid anhydride in trifluoroacetic acid followed bycatalytic reduction analogously to Example Id with 10%palladium/charcoal in methanol.

Yield: 76% of theory,

R_(f) value: 0.6 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

The following compounds were prepared analogously to Example III:

(1) 4-(N-ethoxycarbonylmethyl-N-ethylsulphonyl-amino)-aniline

R_(f) value: 0.5 (silica gel; petroleum ether/ethyl acetate=4:6)

Melting point: 78° C.

C₁₂H₁₈N₂O₄S (286.35)

Mass spectrum: (M+Na)⁺=309, (2M+Na)⁺=593

(2)4-{N-[2-(N-acetyl-N-methyl-amino)-ethyl]-N-methylsulphonyl-amino)-aniline

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/ammonia=19:1:0.1)

(3) 4-[N-(2-acetylamino-ethyl)-N-methylsulphonyl-amino]-aniline

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/ammonia=19:1:0.1)

C₁₁H₁₇N₃O₃S (271.34)

Mass spectrum: (M+H)⁺=272, (M+Na)⁺=294

(4)4-{N-[2-(N-acetyl-N-methyl-amino)-ethyl]-N-ethylsulphonyl-amino}-aniline

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/ammonia=19:1:0.1)

Melting point: 140° C.

C₁₃H₂₁N₃O₃S (299.39)

Mass spectrum: M⁺=299

(5) 4-[N-(2-acetylamino-ethyl)-N-ethylsulphonyl-amino)-aniline

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=19:1:0.1)

C₁₂H₁₉N₃O₃S (285.36)

Mass spectrum: (M−H)⁻=284, (M+Na)⁺=308

(6)4-{N-[2-(N-methyl-N-trifluoroacetyl-amino)-ethyl]-N-methylsulphonyl-amino}-aniline

R_(f) value: 0.5 (silica gel; dichloromethane/ethyl acetate=9:1)

EXAMPLE IV 4-[N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino]-anilinea. N-(2-dimethylamino-ethyl)-phenylsulphonamide

2.8 g (30 mmol) of N,N-dimethylethylenediamine are placed in 100 ml ofdichloromethane and 8.3 ml (60 mmol) of triethylamine. While coolingwith ice a solution of 3.9 ml (30 mmol) of benzenesulphonic acidchloride in 100 ml of dichloromethane is added dropwise and the mixtureis stirred overnight at ambient temperature. Water is added and themixture is extracted with dichloromethane. The organic phase is driedand evaporated down.

Yield: 6.8 g (99% of theory),

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₀H₁₆N₂O₂S (228.23)

Mass spectrum: (M−H)⁻=227, (M+H)⁺=229

b. 4-[N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino]-nitrobenzene

6.8 g (29.8 mmol) of N-(2-dimethylamino-ethyl)-phenylsulphonamide aredissolved in 100 ml of DMF and combined with 1.3 g (30 mmol) of sodiumhydride (55% in oil). The mixture is stirred for one hour at ambienttemperature. Then 4.2 g (29.8 mmol) of 4-fluoro-nitrobenzene are added,and stirring is continued for another 16 hours. After the addition of300 ml of water the mixture is extracted with ethyl acetate. The organicphase is washed with water, dried and evaporated down. The residue isacidified with 1 N hydrochloric acid and washed with ethyl acetate. Theaqueous phase is then made basic again with sodium hydroxide solutionand extracted with ethyl acetate. The organic phase is dried andevaporated down.

Yield: 6.0 g (58% of theory),

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₆H₁₉N₃O₄S (349.41)

Mass spectrum: (M−H)⁻=348, (M+H)⁺=350

c. 4-[N-(2-dimethylaminoethyl)-N-phenylsulphonyl-amino]-aniline

Prepared analogously to Example Id by catalytic hydrogenation of 6 g(17.2 mmol) of4-[N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino]-nitrobenzene.

Yield: 5.5 g (99% of theory),

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₆H₂₁N₃O₂S (319.43)

Mass spectrum: (M+H)⁺=320

The following compounds were prepared analogously to Example IV:

(1) 4-[N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino]-aniline

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₃H₂₃N₃O₂S (285.41)

Mass spectrum: (M+H)⁺=286, (M−H)⁻=284

(2) 4-[N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino]-aniline

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₄H₂₅N₃O₂S (299.43)

Mass spectrum: (M+H)⁺=300

(3) 4-[N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino]-aniline

Melting point: 112–113° C.

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₂H₂₁N₃O₂S (271.38)

Mass spectrum: (M+H)⁺=272, (M+Na)⁺=294

(4) 4-[N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-amino]-aniline

R_(f) value: 0.3 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₇H₂₃N₃O₂S (333.46)

Mass spectrum: (M+H)⁺=334, (M+Na)⁺=356

(5)3-chloro-4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline

Melting point: 145–148° C.

R_(f) value: 0.5 (silica gel; dichloromethane/ethanol/ammonia=5:1:0.01)

C₁₁H₁₈ClN₃O₂S (291.80)

Mass spectrum: (M+H)⁺=294, 292, (M−H)⁻=292, 290

(6)3-amino-4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline

R_(f) value: 0.3 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₁H₂₀N₄O₂S (272.37)

Mass spectrum: (M+H)⁺=273

(7) 4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline

R_(f) value: 0.3 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

Melting point: 147–148° C.

C₁₁H₁₉N₃O₂S (257.36)

Mass spectrum: (M+H)⁺=258, (M+Na)⁺=280

EXAMPLE V 3-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-anilinea. 3-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-nitrobenzene

5 g (23.1 mmol) of 3-methylsulphonylamino-nitrobenzene are dissolved in50 ml of DMSO and combined with 6.5 g (58 mmol) of potassium tertbutoxide while cooling with ice. The solution thus obtained is addeddropwise to a solution of 5 g (34.7 mmol) of2-chloro-N,N-dimethyl-ethylamine in 30 ml of DMSO. The mixture isstirred for 2 hours at ambient temperature and then heated for 6 hoursto 100° C. After cooling to ambient temperature 400 ml of water areadded. The mixture is extracted with ethyl acetate. Water and 1 Nhydrochloric acid are added to the combined organic phases until an acidreaction is obtained. The aqueous phase is washed with ethyl acetate.Then the aqueous phase is made alkaline with sodium carbonate and theproduct is extracted with ethyl acetate. Drying the combined organicphases over magnesium sulphate and eliminating the solvents in vacuoyields the product as a red oil.

Yield: 2.07 g (31% of theory),

R_(f) value: 0.3 (silica gel; ethyl acetate/methanol=4:1)

C₁₁H₁₇N₃O₄S (287.34)

Mass spectrum: (M−H)⁻=286, (M+H)⁺=288

b. 3-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline

Prepared analogously to Example 1d by catalytic hydrogenation of 1.9 g(6.8 mmol) of3-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-nitrobenzene overpalladium/charcoal.

Yield: 1.8 g (99% of theory),

R_(f) value: 0.3 (silica gel; ethyl acetate/methanol/NH₄OH=8:2:0.1)

C₁₁H₁₉N₃O₂S (257.36)

Mass spectrum: (M−H)⁻=256, (M+H)⁺=258

EXAMPLE VI 4-(4-benzyl-piperazinomethyl)-aniline a.4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene

A mixture of 10.6 g (57 mmol) of N-tert.butoxycarbonyl-piperazine, 10.8g (62.7 mmol) of 4-nitrobenzylchloride, 23.8 ml (171 mmol) oftriethylamine in 100 ml of dichloromethane is stirred for 12 hours at70° C. After diluting with water the organic phase is separated off,dried and evaporated down.

Yield: 19 g (99% of theory),

Melting point: 83–84° C.

R_(f) value: 0.7 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₆H₂₃N₃O₄ (321.38)

Mass spectrum: (M+H)⁺=322, (M−H)⁻=320

b. 4-piperazinomethyl-nitrobenzene-dihydrochloride

6.4 g (20 mmol) of4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene are dissolved in20 ml of dichloromethane and combined with 40 ml of ethyl acetate/HCl.The reaction solution is diluted with ether, the precipitate formed issuction filtered as a crude product and then reacted further.

Yield: 5.4 g (92% of theory),

Melting point: 257–258° C.

R_(f) value: 0.3 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

c. 4-(4-benzylpiperazinomethyl)-nitrobenzene

The free base is produced from 1.5 g (5 mmol) of4-piperazinomethyl-nitrobenzene-dihydrochloride by dissolving in 25 mlof 1 N sodium hydroxide solution, extracting with ethyl acetate and theneliminating the solvent in vacuo. The solid thus obtained is combinedwith 2.5 ml of 2 N acetic acid, 0.5 ml (5.5 mmol) of benzaldehyde and 50ml of methanol and, after the addition of 0.7 g (5 mmol) of sodiumcyanoborohydride, stirred for 2 hours. Then the pH is adjusted to acidwith 1 N hydrochloric acid and the reaction solution is washed withether. The aqueous phase is then made basic with sodium hydroxidesolution. The product is extracted with ether, the combined etherextracts are dried and the solvent is eliminated in vacuo.

Yield: 1.3 g (84% of theory),

R_(f) value: 0.6 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₈H₂₁N₃O₂ (311.39)

Mass spectrum: (M+H)⁺=312

d. 4-(4-benzylpiperazinomethyl)-aniline

Prepared analogously to Example Id by catalytic hydrogenation of 1.3 g(4.2 mmol) of 4-(4-benzylpiperazinomethyl)-nitrobenzene overpalladium/charcoal.

Yield: 1.2 g (87% of theory),

Melting point: 88–89° C.

C₁₈H₂₃N₃ (281.4)

Mass spectrum: (M+H)⁺=282

EXAMPLE VII 4-(4-tert.butoxycarbonyl-piperazinomethyl)-aniline a.4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene

10.6 g (57 mmol) of N-tert.butoxycarbonyl-piperazine are dissolved in100 ml of dichloromethane and combined with 10.7 g (63 mmol) of4-nitrobenzylchloride and 24 ml (171 mmol) of triethylamine. The mixtureis refluxed for 12 hours. After cooling to ambient temperature thereaction solution is washed several times with water. The organic phaseis dried over magnesium sulphate and then evaporated to dryness.

Yield: 17 g (99%) of theory

Melting point: 83–84° C.

R_(f) value: 0.7 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₆H₂₃N₃O₄ (321.38)

Mass spectrum: (M+H)⁺=322, (M−H)⁻=320

b. 4-(4-tert.butoxycarbonyl-piperazinomethyl)-aniline

Prepared analogously to Example Id by catalytic hydrogenation of4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene with Raneynickel in ethyl acetate/methanol (1:1).

Melting point: 106–107° C.

R_(f) value: 0.6 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₆H₂₅N₃O₂ (291.39)

Mass spectrum: (M+H)⁺=292, (M+Na)⁺=314

The following compounds were prepared analogously to Example VII:

(1) 4-(pyrrolidin-1-yl-methyl)-aniline

R_(f) value: 0.2 (silica gel; dichloromethane/methanol/NH₄OH=5:1:0.01)

Melting point: 48–50° C.

(2) 4-(4-methylpiperazinomethyl)-aniline

Melting point: 94–95° C.

R_(f) value: 0.2 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₁₂H₁₉N₃ (205.31)

Mass spectrum: (M+H)⁺=206

(3) 3-(dimethylaminomethyl)-aniline

R_(f) value: 0.7 (silica gel; ethyl acetate)

Melting point: 43–46° C.

(4) 4-(dimethylaminomethyl)-aniline

R_(f) value: 0.13 (silica gel; ethyl acetate/ethanol=8:2)

(5) 4-(2-dimethylamino-ethyl)-aniline

R_(f) value: 0.3 (silica gel; dichloromethane/methanol/ammonia=19:1:0.1)

Melting point: 40° C.

C₁₀H₁₆N₂ (164.25)

Mass spectrum: (M+H)⁺=165

(6) 4-(N-benzyl-N-methyl-aminomethyl)-aniline

R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=10:1:0.01)

Melting point: 48–50° C.

C₁₅H₁₈N₂ (226.32)

Mass spectrum: (M+H)⁺=227

(7) 4-piperidinomethyl-aniline

R_(f) value: 0.2 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

Melting point: 88–89° C.

(8) 4-(2,6-dimethylpiperidino-methyl)-aniline

R_(f) value: 0.3 (silica gel; dichloromethane/methanol/ammonia=5:1:0.01)

Melting point: 112–115° C.

(9) 4-(N-ethyl-N-methyl-aminomethyl)-aniline

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=10:1:0.1)

C₁₀H₁₆N₂ (164.25)

Mass spectrum: (M+H)⁺=165

(10)4-[4-(3-trifluoromethylcarbonylamino-propyl)-piperidinomethyl]-aniline

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=10:1:0.1)

C₁₇H₂₄F₃N₃O (343.40)

Mass spectrum: (M+H)⁺=344

(11) 4-(N-tert.butoxycarbonyl-N-propyl-aminomethyl)-aniline C₁₅H₂₄N₂O₂(264.37)

Mass spectrum: (M+Na)⁺=287

(12) 4-(N-tert.butoxycarbonyl-N-butyl-aminomethyl)-aniline

R_(f) value: 0.19 (silica gel; dichloromethane/methanol=50:1)

C₁₆H₂₆N₂O₂ (278.40)

Mass spectrum: (M+Na)⁺=301

(13) 4-(N-tert.butoxycarbonyl-N-ethyl-aminomethyl)-aniline

Melting point: 85° C.

R_(f) value: 0.3 (silica gel; dichloromethane/methanol/=50:1)

C₁₄H₂₂N₂O₂ (250.34)

Mass spectrum: (M+Na)⁺=273

EXAMPLE VII 4-(2-oxopiperidinomethyl)-aniline

6.4 g (42 mmol) of 4-nitrobenzaldehyde are dissolved in 150 ml ofmethanol and combined with 4.9 g (42 mmol) of 5-aminovaleric acid and1.8 g (29 mmol) of sodium cyanoborohydride. The mixture is stirred for18 hours at ambient temperature and then carefully mixed with 20 ml ofconc. hydrochloric acid. The solvent is eliminated in vacuo, the residueis taken up in water and extracted with dichloromethane. The residueobtained after evaporation is chromatographed on silica gel(dichloromethane/methanol, 4:1). A mixture of methyl5-(4-nitrobenzylamino)-pentanoate and4-(2-oxopiperidinomethyl)-nitrobenzene is obtained which is dissolved in100 methanol and combined with 50 ml of 1 N sodium hydroxide solution.The mixture is stirred for one hour at ambient temperature, 50 ml of 1 Nhydrochloric acid are added and the reaction solution is evaporated downto 100 ml. The aqueous phase thus obtained is extracted withdichloromethane. The combined organic phases are dried over sodiumsulphate and evaporated to dryness.

The residue is hydrogenated analogously to Example Id over Raney nickelin methanol under a hydrogen atmosphere of 3 bar for 11 hours.

Total yield: 2.2 g (26% of theory),

R_(f) value: 0.63 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE IX 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-aniline a.4-(N-bromomethylcarbonyl-N-methyl-amino)-nitrobenzene

23.5 g (0.15 mol) of N-methyl-4-nitroaniline are dissolved in 400 ml ofdioxane and combined with 22.2 g (0.3 mol) of lithium carbonate. Then32.2 g (0.18 mol) of bromoacetylbromide are added dropwise in such a waythat the internal temperature does not exceed 33° C. After 18 hours'stirring the reaction solution is evaporated down to 100 ml, combinedwith 500 ml of water and stirred for 1 hour. The precipitate formed issuction filtered, washed with water and dried. The crude product isstirred in 400 ml of ethyl acetate at 40° C. Then the insoluble matteris filtered off, the solution is evaporated down and the solid residueis triturated with ether.

Yield: 35 g (83% of theory),

Melting point: 85–87° C.

b. 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-nitrobenzene

5.4 g (20 mmol) of 4-(N-bromomethylcarbonyl-N-methyl-amino)-nitrobenzeneare dissolved in 100 ml of acetone and combined with 5.5 g (40 mmol) ofpotassium carbonate. 3 ml (30 mmol) of piperidine are slowly addeddropwise and the mixture is stirred for 18 hours at ambient temperature.The reaction solution is filtered, and the filtrate is evaporated todryness. The residue is dissolved in ethyl acetate, washed with water,dried over magnesium sulphate and evaporated to dryness.

Yield: 5.6 g (99% of theory).

c. 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-aniline

Prepared analogously to Example Id by catalytic hydrogenation of4-(N-piperidinomethylcarbonyl-N-methyl-amino)-nitrobenzene in methanolover palladium/charcoal.

Yield 4.95 g (99% of theory)

EXAMPLE X 4-(tert.butoxycarbonylaminomethyl)-aniline

20 g (164 mmol) of 4-aminobenzylamine and 20.2 g (210 mmol) oftriethylamine are dissolved in 100 ml of dioxane and 50 ml of water.35.8 g (165 mmol) of di-tert.butyl-dicarbonate dissolved in 60 ml ofdioxane are added to this solution while cooling with ice and theresulting mixture is stirred for 18 hours at ambient temperature. Thenthe solvent is distilled off in vacuo, the residue is distributed inethyl acetate/water. The combined organic extracts are freed fromsolvent in vacuo. The crude product is heated in 200 ml of petroleumether, cooled slowly with vigorous stirring and the crystalline productis removed by suction filtering.

Yield: 34.8 g (96% of theory),

Melting point: 77–78° C.

EXAMPLE XI 4-(1H-imidazol-2-yl)-aniline

7.2 g (50 mmol) of 2-phenylimidazol are dissolved in 100 ml of conc.sulphuric acid. While cooling with ice 5.0 g (62 mmol) of ammoniumnitrate are added in batches and the mixture is stirred for 2.5 hours.The reaction solution is then poured onto ice, made basic with conc.ammonia and the crystalline product is suction filtered. The nitrocompound thus obtained is catalytically hydrogenated analogously toExample Id in DMF over palladium/charcoal.

Yield: 24% of theory,

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

EXAMPLE XII Pyridine-2-sulphonic acid chloride

5.0 g (45 mmol) of pyridine-2-thiol are dissolved in 40 ml of conc.hydrochloric acid. While the solution is cooled with ice, chlorine gasis piped in over a period of 2.5 hours. In order to destroy any excessgas a washing bottle containing 1 N sodium thiosulphate solution isattached. Then the reaction solution is poured onto ice water andextracted with ether and dichloromethane. The organic phases arecombined, dried and freed from solvent in vacuo. The crude product isfurther reacted immediately.

Yield: 8 g (100% of theory).

EXAMPLE XIII Pyridine-3-sulphonic acid chloride hydrochloride

1 g (6.3 mmol) of pyridine-3-sulphonic acid and 1.4 g (6.7 mmol) ofphosphorus pentachloride are stirred for 2 hours at 150° C. Aftercooling, excess phosphorus pentachloride is eliminated in vacuo. Thecrude product is further reacted immediately.

Yield: 1.2 g (91% of theory).

Preparation of the end products:

EXAMPLE 1(Z)-3-{1-[4-(N-acetyl-N-(2-aminoethyl)-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinonea. 1-acetyl-2-indolinone

13.3 g (0.1 mol) of 2-indolinone and 30 ml of acetic anhydride arestirred for 3 hours at 170° C. After cooling the mixture is combinedwith 150 ml of ice water, the crystalline product is suction filtered,washed with water and dried.

Yield: 16.6 g (95% of theory),

Melting point: 129–130° C.

b. 1-acetyl-5-nitro-2-indolinone

0.5 g (2.8 mmol) of 1-acetyl-2-indolinone are placed in 4 ml of conc.sulphuric acid. At a temperature of −10 to −5° C., 0.3 g (3.4 mmol) ofammonium nitrate are added in batches. After 45 minutes the mixture ispoured onto ammonia/ice water, the crystalline precipitate is suctionfiltered, washed with water and dried. The crude product isrecrystallised from 70 ml of cyclohexane.

Yield: 0.2 g (32% of theory),

Melting point: 150–157° C.

R_(f) value: 0.7 (silica gel; cyclohexane/ethyl acetate=4:6)

c. 1-acetyl-5-amino-2-indolinone

30.0 g (136 mmol) of 1-acetyl-5-nitro-2-indolinone are dissolved in amixture of 650 ml of dichloromethane and 650 ml of methanol and afterthe addition of 5 g of 10% palladium on activated charcoal the mixtureis hydrogenated for 45 minutes with hydrogen. Then the catalyst isfiltered off and evaporated down.

Yield: 22.4 g (87% of theory),

Melting point: 177° C.

R_(f) value: 0.7 (silica gel; ethyl acetate)

C₁₀H₁₀N₂O₂ (190.20)

Mass spectrum: (M−H)⁻=189, (M+Na)⁺=213

d. 1-acetyl-5-phenylsulphonylamino-2-indolinone

20.0 g (105 mmol) of 1-acetyl-5-amino-2-indolinone are placed in 200 mlof pyridine, combined with 15.3 ml (120 mmol) of benzenesulphonic acidchloride while cooling with ice and stirred for 2 hours. Then themixture is poured onto 1.81 of water and suction filtered. The crudeproduct is stirred into acetone, suction filtered and dried.

Yield: 30.5 g (88% of theory),

Melting point: 245° C.

R_(f) value: 0.5 (silica gel; dichloromethane/ethyl acetate=9:1)

C₁₆H₁₄N₂O₄S (330.37)

Mass spectrum: (M−H)⁻=329, (M+Na)⁺=353

e.1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone

8.0 g (24.2 mmol) of 1-acetyl-5-phenylsulphonylamino-2-indolinone aredissolved in 150 ml of acetic anhydride and after the addition of 20 ml(88.1 mmol) of triethyl orthobenzoate refluxed for 6 hours. The solventis distilled off, the residue is triturated with ether, suction filteredand dried.

Yield: 7.8 g (64% of theory),

Melting point: 237° C.

R_(f) value: 0.7 (silica gel; dichloromethane/ethyl acetate=19:1)

C₂₇H₂₄N₂O₆S (504.57)

Mass spectrum: M⁺=504

f.(Z)-3-{1-[4-(N-acetyl-N-(2-aminoethyl)-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone

A mixture of 0.5 g (1 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinoneand 0.3 g (1.2 mmol) of4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-aniline are stirredin 5 ml of DMF for 6 hours at 120° C. After cooling to ambienttemperature 5 ml of methanol and 3 ml (6 mmol) of 2 N sodium hydroxidesolution are added, and the mixture is stirred for 30 minutes. Thereaction mixture is diluted with 50 ml of water and the crystallineprecipitate is suction filtered and dried. The residue ischromatographed on silica gel(dichloromethane/methanol/ammonia=9:1:0.1).

Yield: 0.3 g (49% of theory),

Melting point: 216° C.

R_(f) value: 0.3 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

C₃₁H₂₉N₅O₄S (567.67)

Mass spectrum: (M−H)⁻=566, (M+H)⁺=568

EXAMPLES 2 to 97

Using the intermediate products prepared in Examples I to XIII, thecompounds of formula IA of Examples 2 to 97 listed in Table I areprepared analogously to Example 1.

TABLE I (IA)

Melting point Example R₂ R₇ R₉ chemical name (° C.) phenylN-(2-aminoethyl)-N- H (Z)-3-{1-[4-(N-(2-aminoethyl)-N-methylsulphonyl-245 methylsulphonyl- amino)-phenylamino]-1-phenyl-methylidene}-5- aminophenylsulphonylamino-2-indolinone phenyl N-(2-methylamino- H(Z)-3-{1-[4-(N-(2-methylamino-ethyl)-N- 227–229 ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N- 168–169ethyl)-N- phenylsulphonyl-amino)-phenylamino)-1-phenyl- phenylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 137–138ethyl)-N- propylsulphonyl-amino)-phenylamino]-1-phenyl- propylsuphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 197–198ethyl)-N- butylsulphonyl-amino)-phenylamino]-1-phenyl-butylsulphonyl-amino methylidene}-5-phenylsulphonylamino-2-indolinonephenyl 4-benzyl-piperazino- H (Z)-3-{1-[4-(4-benzyl-piperazinomethyl)-130 methyl phenylamino]-1-phenyl-methylidene}-5- (decomp.)phenylsulphonylamino-2-indolinone phenyl N-acetyl-N-(2-benzyl- H(Z)-3-{1-[4-(N-acetyl-N-(2-benzyloxycarbonylamino- 180 oxycarbonylamino-ethyl)-amino)-phenylamino]-1-phenyl-methylidene}-5- ethyl)-aminophenylsulphonyl-amino-2-indolinone phenyl 4-methylpiperazino- H(Z)-3-{1-[4-(4-methylpiperazinomethyl)- 243–244 methylphenylamino]-1-phenyl-methylidene}-5- phenylsulphonylamino-2-indolinonephenyl morpholinomethyl H (Z)-3-{1-[4-(morpholinomethyl)-phenylamino]-1-243–244 phenyl-methylidene}-5-phenylsulphonylamino-2- indolinone phenyl2- H (Z)-3-{1-[4-(2-oxopiperidinomethyl)-phenylamino]-1- 311–312oxopiperidinomethyl phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl pyrrolidin-1-ylmethyl H(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1- 228–229phenyl-methylidene}-5-phenylsulphonylamino-2- indolinone phenyl4-tert.butoxycarbonyl- H(Z)-3-{1-[4-(4-tert.butoxycarbonyl-piperazinomethyl)- 160–161piperazinomethyl phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-methyl-N-formyl- H(Z)-3-{1-[4-(N-methyl-N-formyl-amino)- 315–317 aminophenylamino]-1-phenyl-methylidene}-5- phenylsulphonylamino-2-indolinonephenyl tert.butoxycarbonyl- H(Z)-3-[1-(4-tert.butoxycarbonylamino-phenylamino)-1- 96–98 aminophenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-methyl-N- H (Z)-3-{1-[4-(N-methyl-N-propionyl-amino)- 208–210propionyl-amino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl acetylamino H(Z)-3-[1-(4-acetylamino-phenylamino)-1-phenyl- 245–247methylidene]-5-phenylsulphonylamino-2-indolinone phenyl N-methyl-N- H(Z)-3-{1-[4-(N-methyl-N-ethylsulphonyl-amino)- 278–280ethylsulphonyl-amino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl propionylamino H(Z)-3-[1-(4-propionylamino-phenylamino)-1-phenyl- 254–256methylidene]-5-phenylsulphonylamino-2-idolinone phenylN-methyl-N-acetyl- H (Z)-3-{1-[4-(N-methyl-N-acetyl-amino)- 283–285amino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-acetyl-N-[2-(N- H(Z)-3-{1-[4-(N-acetyl-N-(2-(N-benzyl-N-methyl- 237 benzyl-N-methyl-amino)-ethyl)-amino)-phenylamino]-1-phenyl- amino)-ethyl]-aminomethylidene}-5-phenylsulphonylamino-2-indolinone phenyl H H(Z)-3-(1-phenylamino-1-phenyl-methylidene)-5- 283phenylsulphonylamino-2-indolinone phenyl chloro H(Z)-3-[1-(4-chlorophenylamino)-1-phenyl- 295methylidene]-5-phenylsulphonylamino-2-indolinone phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 234ethyl)-N- methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-acetyl-202 ethyl)-N-acetyl-amino amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-piperidinomethyl- H(Z)-3-{1-[4-(N-piperidinomethylcarbonyl-N-methyl- 269 carbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5- aminophenylsulphonylamino-2-indolinone phenyl H N-(2-(Z)-3-{1-[3-(N-(2-dimethylamino-ethyl)-N- 140 dimethylamino-methylsulphonyl-amino)-phenylamino]-1-phenyl- ethyl)-N-methyl-methylidene}-5-phenylsulphonylamino-2-indolinone sulphonyl-amino phenylH dimethylamino- (Z)-3-[1-(3-dimethylaminomethyl-phenylamino)-1- 140methyl phenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-(2-acetylamino- H (Z)-3-{1-[4-(N-(2-acetylamino-ethyl)-N-acetyl- 229ethyl)-N-acetyl-amino amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-(2-acetylamino- H(Z)-3-{1-[4-(N-(2-acetylamino-ethyl)-N-propionyl- 278ethyl)-N-propionyl- amino)-phenylamino]-1-phenyl-methylidene}-5- aminophenylsulphonylamino-2-indolinone phenyl N-(2-propionylamino- H(Z)-3-{1-[4-(N-(2-propionylamino-ethyl)-N-propionyl- 280ethyl)-N-propionyl- amino)-phenylamino]-1-phenyl-methylidene}-5- aminophenylsulphonylamino-2-indolinone phenyl N-[2-(N-acetyl-N- H(Z)-3-{1-[4-(N-(2-(N-acetyl-N-methyl-amino)-ethyl)- 180methyl-amino)-ethyl]- N-methylsulphonyl-amino)-phenylamino]-1-phenyl-(decomp.) N-methylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-acetylamino- H (Z)-3-{1-[4-(N-(2-acetylamino-ethyl)-N- 171ethyl)-N- methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino] phenyl4-{N-[2-(N-acetyl-N- H(Z)-3-{1-[4-(N-(2-(N-acetyl-N-methyl-amino)-ethyl)- 216methyl-amino)-ethyl]- N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-N-ethylsulphonyl- methylidene}-5-phenylsulphonylamino-2-indolinone aminophenyl cyano H (Z)-3-[1-(4-cyanophenylamino)-1-phenyl- 291–293methylidene]-5-phenylsulphonylamino-2-indolinone phenyldimethylaminomethyl H (Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-255–256 phenyl-methylidene]-5-phenylsulphonylamino-2- indole phenyl2-dimethylamino- H (Z)-3-[1-(4-(2-dimethylamino-ethyl)-phenylamino)-1-302–303 ethyl phenyl-methylidene]-5-phenylsulphonylamino-2- indolinonephenyl N-(2-acetylamino- H (Z)-3-{1-[4-(N-(2-acetylamino-ethyl)-N- 158ethyl)-N- ethylsulphonyl-amino)-phenylamino]-1-phenyl-ethylsulphonyl-amino methylidene}-5-phenylsulphonylamino-2-indolinonephenyl acetylaminomethyl H (Z)-3-[1-(4-acetylaminomethyl-phenylamino)-1-289–290 phenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-[2-(N-acetyl-N- H (Z)-3-{1-[4-(N-(2-(N-acetyl-N-methyl-amino)-ethyl)-297 methyl-amino)-ethyl]- N-acetyl-amino)-phenylamino]-1-phenyl-N-acetyl-amino methylidene}-5-phenylsulphonylamino-2-indolinone phenylmethylsulphonylamino H (Z)-3-[1-(4-methylsulphonylamino-phenylamino)-1-258–260 phenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-methyl-N- H (Z)-3-[1-(4-(N-methyl-N-methylsulphonyl-amino)- 306–308methylsulphonyl- phenylamino)-1-phenyl-methylidene]-5- aminophenylsulphonylamino-2-indolinone phenyl ethylsulphonylamino H(Z)-3-[1-(4-ethylsulphonylamino-phenylamino)-1- 177–179phenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-[2-(N-acetyl-N- H (Z)-3-{1-[4-(N-(2-(N-acetyl-N-methyl-amino)-ethyl)-250 methyl-amino)-ethyl]- N-propionyl-amino)-phenylamino]-1-phenyl-N-propionyl-amino methylidene}-5-phenylsulphonylamino-2-indolinonephenyl N-[2-(N-benzyl-N- H(Z)-3-{1-[4-(N-(2-(N-benzyl-N-methyl-amino)-ethyl)- 220methyl-amino)-ethyl]- N-propionyl-amino)-phenylamino]-1-phenyl-N-propionyl-amino methylidene}-5-phenylsulphonylamino-2-indolinonephenyl dimethylamino- H (Z)-3-{1-[4-(dimethylaminocarbonylmethylamino)-230–231 carbonylmethylamino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl formylamino H(Z)-3-[1-(4-formylamino-phenylamino)-1-phenyl- 305–307methylidene]-5-phenylsulphonylamino-2-indolinone phenyl(2,6-dimethylpiperi- H (Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)-144–145 dino)-methyl phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-(dimethyl- H(Z)-3-{1-[4-(N-dimethylaminomethylcarbonyl-N- 242 aminomethylcarbonyl)-methyl-amino)-phenylamino]-1-phenyl-methylidene}- N-methyl-amino5-phenylsulphonylamino-2-indolinone phenyl N-(2-dimethylamino- H(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 80 (decomp.) ethyl)-N-benzylsulphonyl-amino)-phenylamino]-1-phenyl- benzylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenyl2-propionylamino- H (Z)-3-{1-[4-(2-propionylamino-ethylamino)- 216ethylamino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N- H(Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-propyl- 215 tert.butoxycarbonyl-aminomethyl)-phenylamino]-1-phenyl-methylidene)- N-propyl-5-phenylsulphonylamino-2-indolinone aminomethyl phenyl N- H(Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-butyl- 207 tert.butoxycarbonyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}- N-butyl-aminomethyl5-phenylsulphonylamino-2-indolinone phenyl methyl H(Z)-3-[1-(4-methylphenylamino)-1-phenyl- 192methylidene]-5-phenylsulphonylamino-2-indolinone phenylN-methyl-N-ethyl- H (Z)-3-[1-(4-(N-methyl-N-ethyl-aminomethyl)- 256aminomethyl phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone phenyl N-methyl-N-piperidi- H(Z)-3-[1-(4-(N-methyl-N-piperidinomethylcarbonyl- 274–276nomethylcarbonyl- amino)-phenylamino)-1-phenyl-methylidene]-5- aminophenylsulphonylamino-2-indolinone benzyl dimethylaminomethyl H(Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1- 242–243phenyl-methylidene}-5-benzylsulphonylamino-2- indolinone benzylpyrrolidin-1-ylmethyl H(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1- 228phenyl-methylidene}-5-benzylsulphonylamino-2- indolinone benzyltert.butoxycarbonyl- H (Z)-3-[1-(4-tert.butoxycarbonylaminomethyl- 205aminomethyl phenylamino)-1-phenyl-methylidene]-5-benzylsulphonylamino-2-indolinone benzyl (2,6-dimethylpiperidi- H(Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)- 140 no)-methylphenylamino]-1-phenyl-methylidene}-5- (decomp.)benzylsulphonylamino-2-indolinone 3- (2,6-dimethylpiperidi- H(Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)- 186 methoxy- no)-methylphenylamino]-1-phenyl-methylidene}-5-(3- phenylmethoxyphenylsulphonylamino)-2-indolinone 3- pyrrolidin-1-ylmethyl H(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1- 233 methoxy-phenyl-methylidene}-5-(3- phenylmethoxyphenylsulphonylamino)-2-indolinone 3- tert.butoxycarbonyl- H(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl- 189 methoxy- aminomethylphenylamino)-1-phenyl-methylidene]-5-(3- phenylmethoxyphenylsulphonylamino)-2-indolinone 3-nitro- pyrrolidin-1-ylmethylH (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino)-1- 181 phenylphenyl-methylidene}-5-(3- nitrophenylsulphonylamino)-2-indolinone3-nitro- tert.butoxycarbonyl- H(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl)- 238° C. phenyl aminomethylphenylamino)-1-phenyl-methylidene]-5-(3- (decomp.)nitrophenylsulphonylamino)-2-indolinone 3-nitro- (2,6-dimethylpiperidi-H (Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)- 215 phenyl no)-methylphenylamino]-1-phenyl-methylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone 2-cyano- 4-methylpiperazino- H(Z)-3-{1-[4-(4-methylpiperazinomethyl)- 255 phenyl methylphenylamino]-1-phenyl-methylidene}-5-(2- (decomp.)cyanophenylsulphonylamino)-2-indolinone 3-amino- 4-methylpiperazino- H(Z)-3-{1-[4-(4-methylpiperazinomethyl)- 278 carbonyl- methylphenylamino]-1-phenyl-methylidene}-5-(3- (decomp.) phenylaminocarbonyl-phenyl sulphonylamino)-2-indolinone ethyl H H(Z)-3-(1-phenylamino-1-phenyl-methylidene)-5- 309ethylsulphonylamino-2-indolinone ethyl dimethylaminomethyl H(Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1- 230phenyl-methylidene}-5-ethylsulphonylamino-2- indolinone ethylN-benzyl-N-methyl- H (Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)- 223aminomethyl phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone ethyl 2-dimethylamino- H(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1- 242 ethylphenyl-methylidene}-5-ethylsulphonylamino-2- indolinone ethylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 240ethyl)-N-methyl- methylsulphonyl-amino)-phenylamino]-1-phenyl-sulphonyl-amino methylidene}-5-ethylsulphonylamino-2-indolinone ethyl ClH (Z)-3-[1-(4-chlorophenylamino)-1-phenyl- 274methylidene]-5-ethylsulphonylamino-2-indolinone ethyl nitro H(Z)-3-{1-[4-nitrophenylamino]-1-phenyl- 270methylidene}-5-ethylsulphonylamino-2-indolinone phenyl N- H(Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-ethyl- 225 tert.butoxycarbonyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}- N-ethyl-aminomethyl5-phenylsulphonylamino-2-indolinone ethyl 4-(3-aminopropyl)- H(Z)-3-{1-[4-(4-(3-aminopropyl)-piperidinomethyl)- 224 piperidinomethylphenylamino]-1-phenyl-methylidene}-5- ethylsulphonylamino-2-indolinoneethyl 4-(3-acetylamino- H (Z)-3-{1-[4-(4-(3-acetylamino-propyl)- 145propyl)- piperidinomethyl)-phenylamino]-1-phenyl- piperidinomethylmethylidene}-5-ethylsulphonylamino-2-indolinone pyridin-3-dimethylaminomethyl H (Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1-246–247 yl phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- pyrrolidin-1-ylmethyl H(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1- 235–236 ylphenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)- 2-indolinonepyridin-3- N-acetyl-N-methyl- H (Z)-3-{1-[4-(N-acetyl-N-methyl-amino)-240–241 yl amino phenylamino]-1-phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- N-methyl-N- H(Z)-3-{1-[4-(N-methyl-N-methylsulphonyl-amino)- 286–287 ylmethylsulphonyl- phenylamino]-1-phenyl-methylidene}-5-(pyridin-3- aminoyisulphonylamino)-2-indolinone pyridin-3- N-(2-dimethylamino- H(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 249–250 yl ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2- amino indolinonepyridin-3- 1H-imidazol-2-yl H(Z)-3-{1-[4-(1H-imidazol-2-yl)-phenylamino]-1- 222–223 ylphenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)- 2-indolinonepyridin-3- 1-methyl-1H- H (Z)-3-{1-[4-(1-methyl-1H-imidazol-2-yl)-230-231 yl imidazol-2-ylphenylamino]-1-phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- dimethylamino- H(Z)-3-{1-[4-dimethylaminocarbonyl-phenylamino]-1- 171–172 yl carbonylphenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)- 2-indolinonepyridin-3- 4-methyl- H (Z)-3-{1-[4-(4-methylpiperazinomethyl)- 258–259yl piperazinomethyl phenylamino]-1-phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- pyrrolidin-1- H(Z)-3-{1-[4-(pyrrolidin-1-ylcarbonyl)-phenylamino]-1- 284–285 ylylcarbonyl phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- N-(2-dimethylamino- Cl(Z)-3-{1-[3-chloro-4-(N-(2-dimethylamino-ethyl)-N- 261–262 yl ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2- amino indolinonepyridin-3- N-(2-dimethylamino- NH₂(Z)-3-{1-[3-amino-4-(N-(2-dimethylamino-ethyl)-N- 272–273 yl ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2- amino indolinonepyridin-2- 4-methyl- H (Z)-3-{1-[4-(4-methylpiperazinomethyl)- 210 ylpiperazinomethyl phenylamino]-1-phenyl-methylidene}-5-(pyridin-2-(decomp.) ylsulphonylamino)-2-indolinone pyridin-2- N-acetyl-N-[2-(N- H(Z)-3-{1-[4-(N-acetyl-N-(2-(N-benzyl-N-methyl- 232–235 ylbenzyl-N-methyl- amino)-ethyl)-amino)-phenylamino]-1-phenyl-amino)-ethyl]-amino methylidene}-5-(pyridin-2-ylsulphonylamino)-2-indolinone pyridin-2- N-(3-dimethylamino- H(Z)-3-{1-[4-(N-(3-dimethylamino-propyl)-N- 217–219 ylpropyl)-N-propionyl- propionyl-amino)-phenylamino]-1-phenyl- aminomethylidene}-5-(pyridin-2-ylsulphonylamino)-2- indolinone pyridin-2-N-(3-dimethylamino- H (Z)-3-{1-[4-(N-(3-dimethylamino-propyl)-N- 258–260yl propyl)-N- methylsulphonyl-amino)-phenylamino]-1-phenyl-methylsulphonyl- methylidene}-5-(pyridin-2-ylsulphonylamino)-2- aminoindolinone pyridin-2- N-(3-dimethylamino- H(Z)-3-{1-[4-(N-(3-dimethylamino-propyl)-N- 256–257 yl propyl)-N-propylsulphonyl-amino)-phenylamino]-1-phenyl- propylsulphonyl-methylidene}-5-(pyridin-2-ylsulphonylamino)-2- amino indolinonepyridin-2- N-(2-dimethylamino- H(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 269–271 yl ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-(pyridin-2-ylsulphonylamino)-2- amino] indolinonepyridin-2- N-piperidinomethyl- H(Z)-3-{1-[4-(N-piperidinomethylcarbonyl-N-methyl- 236–237 ylcarbonyl-N-methyl- amino)-phenylamino]-1-phenyl-methylidene}-5- amino(pyridin-2-ylsulphonylamino)-2-indolinone

EXAMPLE 98(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinonea. 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone

0.2 g (0.9 mmol) of 1-acetyl-5-nitro-2-indolinone and 0.6 g (2.7 mmol)of triethyl orthobenzoate are heated to 100° C. in 2 ml of acetic acidanhydride for 1.5 hours. After cooling the mixture is combined withether and the precipitate formed is suction filtered.

Yield: 0.2 g (66% of theory),

Melting point: 244–250° C.

R_(f) value: 0.7 (silica gel; ethyl acetate/cyclohexane=3:2)

b.(Z)-1-acetyl-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

3 g (8.5 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 1.9g (10 mmol) of 4-piperidinomethyl-aniline are heated to 90° C. in 30 mlof DMF for 3.5 hours. After cooling to ambient temperature the reactionsolution is poured onto ice water and extracted with ethyl acetate. Thecombined organic extracts are dried and evaporated down. The residue istriturated with ether and suction filtered.

Yield: 3.5 g (82% of theory),

R_(f) value: 0.6 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

Melting point: 165° C.

c.(Z)-1-acetyl-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-amino-2-indolinone

Prepared analogously to Example VIIb from(Z)-1-acetyl-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneby catalytic reduction over Raney nickel in dichloromethane/methanol(1:1).

Yield: 99% of theory,

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

Melting point: 278–281° C.

C₂₉H₃₀N₄O₂ (466.59)

Mass spectrum: (M+H)⁺=467

d.(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone

466 mg (1 mmol) of(Z)-1-acetyl-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-amino-2-indolinoneare suspended in 15 ml of pyridine, combined with 0.2 ml (2.3 mmol) ofmethanesulphonic acid chloride and stirred for 1.5 hours. Then 6 ml of 1N sodium hydroxide solution are added. After 1 hour 1 ml of piperidineis added and the mixture is stirred overnight. The reaction solution ispoured onto water and the precipitate formed is suction filtered. Theresidue is stirred with ether, suction filtered and dried.

Yield: 290 mg (58% of theory),

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)

Melting point: 266° C.

C₂₈H₃₀N₄O₃S (502.64)

Mass spectrum: (M+H)⁺=503

Calc.: C 66.91 H 6.02 N 11.15 Found: C 66.49 H 6.06 N 11.01

EXAMPLES 99 to 151

Using the intermediate products prepared in Examples I to XIII, thecompounds of formula IB of Examples 99 to 151 listed in Table II areprepared analogously to Example 98.

Hydrochlorides or dihydrochlorides are obtained according to thefollowing general working method: The starting compound is dissolved indichloromethane and combined with ether/HCl. The precipitate formed issuction filtered and dried.

TABLE II (IB)

Melting point Example R₂ R₇ chemical name (° C.) ethyl piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 235methylidene}-5-ethylsulphonylamino-2-indolinone ethyl methoxy(Z)-3-[1-(4-methoxyphenylamino)-1-phenyl-methylidene]-5-ethyl- 283sulphonylamino-2-indolinone isopropyl piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 205methylidene}-5-isopropylsulphonylamino-2-indolinone 4- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 251–253chlorophenyl methylidene}-5-(4-chlorophenylsulphonylamino)-2-indolinone3- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 275–277chlorophenyl methylidene}-5-(3-chlorophenylsulphonylamino)-2-indolinonenaphthalin-1- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 236–237 ylmethylidene}-5-(naphthalin-1-ylsulphonylamino)-2-indolinone 4-piperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-267–269 methylphenylmethylidene}-5-(4-methylphenylsulphonylamino)-2-indolinone 3-piperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-269–271 methylphenyl methylidene}-5-(3-methylphenylsulphonylamino)-2-indolinone 3- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 241–245methoxyphen methylidene)-5-(3-methoxyphenylsulphonylamino)-2-indolinoneyl 2- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 275 chlorophenylmethylidene}-5-(2-chlorophenylsulphonylamino)-2-indolinone 2-nitrophenylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-140 methylidene}-5-(2-nitrophenylsulphonylamino)-2-indolinone 3-piperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-248 cyanophenylmethylidene}-5-(3-cyanophenylsulphonylamino)-2-indolinone 3,5-piperidinomethyl (Z)-3-{1-[4-(piperidinomethy1)-phenylamino]-1-phenyl-240 dimethylisoxamethylidene}-5-(3,5-dimethylisoxazol-4-ylsulphonylamino)-2- zol-4-ylindolinone E-2- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 248 phenylethenylmethylidene}-5-((E)-2-phenylethenylsulphonylamino)-2-indolinone1-methyl-1H- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 230 imidazol-4-ylmethylidene}-5-(1-methyl-1H-imidazol-4-ylsulphonylamino)-2-indolinone-dihydrochloride cyclopropyl piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 231methylidene}-5-cyclopropylsulphonylamino-2-indolinone 2-piperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-239 cyanophenylmethylidene}-5-(2-cyanophenylsulphonylamino)-2-indolinone pyridin-2-ylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-263 methylidene}-5-(pyridin-2-ylsulphonylamino)-2-indolinone phenylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-262 methylidene}-5-phenylsulphonylamino-2-indolinone benzylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-254 methylidene}-5-benzylsulphonylamino-2-indolinone propylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethy1)-pheny1amino]-1-phenyl-188 methylidene}-5-propylsulphonylamino-2-indolinone benzylN-(2-dimethylami-(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl- 163–164no-ethyl)-N-methyl- amino)-phenylamino]-1-phenyl-methylidene}-5-sulphonyl-amino benzylsulphonylamino-2-indolinone isopropyl2-dimethylamino-(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl- 220 ethylmethylidene}-5-isopropylsulphonylamino-2-indolinone propyl2-dimethylamino-(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl- 239–240 ethylmethylidene}-5-propylsulphonylamino-2-indolinone propylN-benzyl-N-methyl-(Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1- 195–197aminomethyl phenyl-methylidene}-5-propylsulphonylamino-2-indolinonemethyl N-benzyl-N-methyl-(Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1- 241–242aminomethyl phenyl-methylidene}-5-methylsulphonylamino-2-indolinonephenyl N-benzyl-N-methyl-(Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1- 148–150aminomethyl phenyl-methylidene}-5-phenylsulphonylamino-2-indolinonebenzyl N-benzyl-N-methyl-(Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1- 200–204aminomethyl phenyl-methylidene}-5-benzylsulphonylamino-2-indolinonebenzyl 2-dimethylamino-(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl- 260–262 ethylmethylidene}-5-benzylsulphonylamino-2-indolinone-hydrochloridepyridin-3-yl piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 236methylidene}-5-(pyridin-3-ylphenylsulphonylamino)-2-indolinone3-nitrophenyl dimethylamino-(Z)-3-{1-[4-(dimethylaminomethyl)-phenylamino]-1-phenyl- 246–247 methylmethylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone 3-methoxy-dimethylamino- (Z)-3-{1-[4-(dimethylaminomethyl)-phenylamino]-1-phenyl-259–260 phenyl methylmethylidene}-5-(3-methoxyphenylsulphonylamino)-2-indolinone3-nitrophenyl dimethylamino-(Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-phenyl- 298–300methyl amino methylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone2-nitrophenyl N-methyl-N-acetyl-(Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-phenyl- 295–297amino methylidene}-5-(2-nitrophenylsulphonylamino)-2-indolinone 3-N-methyl-N-acetyl-(Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-phenyl- 330–332cyanophenyl aminomethylidene}-5-(3-cyanophenylsulphonylamino)-2-indolinone 3-nitrophenyl4-methyl- (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-166–167 piperazinomethylmethylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone pyridin-2-ylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-261 ylmethyl methylidene}-5-(pyridin-2-ylsulphonylamino)-2-indolinonecyclopropyl pyrrolidin-1-(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl- 256 ylmethylmethylidene}-5-cyclopropylsulphonylamino-2-indolinone propylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-247 ylmethyl methylidene}-5-propylsulphonylamino-2-indolinone ethylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-245 ylmethyl methylidene}-5-ethylsulphonylamino-2-indolinone methylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-248 ylmethyl methylidene}-5-methylsulphonylamino-2-indolinone 2-pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-247 fluorophenyl ylmethylmethylidene}-5-(2-fluorophenylsulphonylamino)-2-indolinone 4-pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-244 fluorophenyl ylmethylmethylidene}-5-(4-fluorophenylsulphonylamino)-2-indolinone 3-pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-257 fluorophenyl ylmethylmethylidene}-5-(3-fluorophenylsulphonylamino)-2-indolinone 2-nitrophenylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-185 ylmethyl methylidene}-5-(2-nitrophenylsulphonylamino)-2-indolinone3- pyrrolidin-1-(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl- 249cyanophenyl ylmethylmethylidene}-5-(3-cyanophenylsulphonylamino)-2-indolinone 2-pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-232 cyanophenyl ylmethylmethylidene}-5-(2-cyanophenylsulphonylamino)-2-indolinone

EXAMPLE 152(Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinonea. 3-(1-ethoxy-1-phenyl-methylidene)-5-phenylsulphonylamino-2-indolinone

8 ml of 4 N sodium hydroxide solution are added to a solution of 4.0 g(8 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone(Example 1e) in a mixture of 20 ml of dichloromethane and 20 ml ofethanol and the resulting mixture is stirred for 20 minutes at ambienttemperature. It is then evaporated down to about. 10 ml and 150 ml ofwater are added. The pH is adjusted to 8–9 with 1 N hydrochloric acid.The precipitate formed is suction filtered, washed with water,isopropanol and ether, then dried in vacuo.

Yield: 6.6 g (82% of theory),

Melting point: 292–294° C.

R_(f) value: 0.4 (silica gel; dichloromethane/methanol/NH₄OH=9:1:0.1)

C₂₃H₂₀N₂O₄S (420.49)

Mass spectrum: (M+H)⁺=421, (M−H)⁻=419

b.(Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone

0.84 g (2 mmol) of3-(1-ethoxy-1-phenyl-methylidene)-5-phenylsulphonylamino-2-indolinoneand 0.39 g (2.2 mmol) of 4-ethoxycarbonylmethyl-aniline are dissolved in10 ml of DMF. The mixture is heated to 140° C. for 5 hours. Then wateris added while the mixture is cooled with ice and stirred for 1 hour atambient temperature. The precipitate formed is suction filtered, washedwith water, a little isopropanol and ether, then dried in vacuo.

Yield: 0.95 g (86% of theory),

Melting point: 248–249° C.

C₃₁H₂₇N₃O₅S (553.64)

Mass spectrum: M⁺=553, (M−H)⁻=552

EXAMPLE 153(Z)-3-[1-(4-carboxymethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone

720 mg (1.3 mmol) of(Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinoneare dissolved in a mixture of 20 ml of methanol and 20 ml ofdichloromethane. 4 ml of 1 N sodium hydroxide solution are added and themixture is stirred for 18 hours at ambient temperature and for another 1hour at 40° C. The reaction solution is evaporated down to half thevolume and the pH is adjusted to 4–5 with 1 N hydrochloric acid. Theprecipitate formed is suction filtered, washed with water, a littleisopropanol and ether.

Yield: 620 mg (91% of theory),

Melting point: 305–306° C.

C₂₉H₂₃N₃O₅S (525.59)

Mass spectrum: (M−H)⁻=524

EXAMPLE 154(Z)-3-{1-[4-(benzylaminocarbonylmethyl)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone

A solution of 315 mg (0.6 mmol) of(Z)-3-[1-(4-carboxymethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone,85 mg (0.8 mmol) of benzylamine, 212 mg (0.66 mmol) of TBTU and 1 ml ofN-ethyl-N,N-diisopropyl-amine in 5 ml of DMF is stirred for 3 hours atambient temperature. Then 50 ml of water are added. The yellowprecipitate formed is suction filtered, washed with water, a littleisopropanol and ether, then dried in vacuo.

Yield: 0.3 mg (81% of theory),

Melting point: 219–220° C.

C₃₆H₃₀N₄O₄S (614.73)

Mass spectrum: (M+Na)⁺=637, (M−H)⁻=613

EXAMPLE 155(Z)-3-{1-[4-(N-(aminocarbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone

A solution of 250 mg (0.4 mmol) of(Z)-3-[1-(4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinoneand 82 mg (0.4 mmol) of CDI in 5 ml of DMF is stirred for 1 hour at 50°C. 1 ml of condensed ammonia is added and the mixture is stirred for 5hours at ambient temperature. Then water is added. The yellowprecipitate is suction filtered, washed with water, a little isopropanoland ether, then dried in vacuo.

Yield: 190 mg (76% of theory)

Melting point: 216–217° C.

C₃₀H₂₇N₅O₆S₂ (617.71)

Mass spectrum: (M+Na)⁺=640, (M−H)⁻=616

EXAMPLES 156 to 170

Using the intermediate products prepared in Examples I to XIII, thecompounds of formula IB of Examples 156 to 170 listed in Table III areprepared analogously to Examples 152 to 155.

TABLE III (IB)

Melting point Example R₂ R₇ chemical name (° C.) phenyl methoxycarbonyl(Z)-3-[1-(4-methoxycarbonyl-phenylamino)-1-phenyl- 304–305methylidene]-5-phenylsulphonylamino-2-indolinone phenyl carboxy(Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-5- 312–313phenylsulphonylamino-2-indolinone phenyl benzylaminocarbonyl(Z)-3-{1-[4-(benzylaminocarbonyl)-phenylamino]-1-phenyl- 269–270methylidene}-5-phenylsulphonylamino-2-indolinone methyl methoxycarbonyl(Z)-3-[1-(4-methoxycarbonyl-phenylamino)-1-phenyl- >270methylidene]-5-methylsulphonylamino-2-indolinone methyl carboxy(Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-5- >270methylsulphonylamino-2-indolinone phenyl N-carboxymethyl-N-acetyl-(Z)-3-{1-[4-(N-carboxymethyl-N-acetyl-amino)-phenylamino]- 190–191 amino1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenylN-aminocarbonylmethyl-N-(Z)-3-{1-[4-(N-(aminocarbonylmethyl)-N-acetyl-amino)- 150 (decomp.)acetyl-amino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-methylaminocarbonyl-(Z)-3-{1-[4-(N-methylaminocarbonylmethyl-N-acetyl-amino)- 150 (decomp.)methyl-N-acetyl-aminophenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino- 2-indolinonephenyl N-dimethylaminocarbonyl-(Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-acetyl-amino)- 150(decomp.) methyl)-N-acetyl-amino)phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino- 2-indolinonephenyl N-carboxymethyl-N-(Z)-3-{1-[4-(N-carboxymethyl-N-ethylsulphonyl-amino)- 231–235ethylsulphonyl-aminophenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino- 2-indolinonephenyl N-[N-(2-dimethylamino-(Z)-3-{1-[4-(N-(N-(2-dimethylamino-ethyl)-N-methyl- 147–151ethyl)-N-methyl-amino-aminocarbonylmethyl)-N-ethylsulphonyl-amino)-phenylamino]-carbonylmethyl]-N-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinoneethylsulphonyl-amino phenyl N-[(2-dimethylamino-ethyl)-(Z)-3-{1-[4-(N-((2-dimethylamino-ethyl)- 142–147 aminocarbonylmethyl]-N-aminocarbonylmethyl)-N-ethylsulphonyl-amino)-phenylamino]-ethylsulphonyl-amino1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenylN-carboxylmethyl-N-(Z)-3-{1-{4-(N-carboxylmethyl-N-methylsulphonyl-amino)- 215–216methylsulphonyl-aminophenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino- 2-indolinonephenyl N-methylaminocarbonyl-(Z)-3-{1-[4-(N-methylaminocarbonylmethyl-N- 150 (decomp.)methyl-N-methylsulphonyl-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}- amino5-phenylsulphonylamino-2-indolinone phenyl N-dimethylamino-(Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N- 150 (decomp.)carbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-methylsulphonyl-amino 5-phenylsulphonylamino-2-indolinone

EXAMPLES 171 to 206

The compounds of formula IB of Examples 171 to 206 listed in thefollowing Table IV are obtained from compounds of the abovementionedExamples 1 to 170 by the following general methods A to E or analogouslyto Example 1 or 210:

A: Cleaving of Tert.butoxycarbonyl:

0.6 mmol of the starting compound are dissolved in 5 ml ofdichloromethane. 10 ml of ethyl acetate/HCl are added and the mixture isstirred for 2 hours at ambient temperature. Then a basic pH is obtainedby the addition of sodium hydroxide solution. The organic phase iswashed with water, dried over sodium sulphate and the solvent iseliminated in vacuo. In order to prepare hydrochlorides the addition ofsodium hydroxide solution is omitted. In order to preparehydrotrifluoroacetate, trifluoroacetic acid is added to the solution ofthe starting compound.

B: Cleaving of Benzyl:

1.5 mmol of the starting compound are dissolved in 20 ml ofdichloromethane/methanol (1:1). 100 mg of palladium/charcoal (10%) and1.5 ml of 1 N hydrochloric acid are added and the mixture is thenhydrogenated in a hydrogen atmosphere at 50 psi. The catalyst is suctionfiltered and the filtrate is evaporated to dryness. The residue ischromatographed on silica gel (dichloromethane/methanol/NH₄OH, 9:1:0.1).

C: Hydrogenation of Cyano to CH₂NH₂:

0.5 mmol of the starting compound are dissolved in 20 ml of methanolicammonia solution and combined with Raney nickel. The mixture ishydrogenated in a hydrogen atmosphere of 50 psi, then the catalyst issuction filtered and the solvent is eliminated in vacuo. The residue ischromatographed on silica gel (dichloromethane/methanol/NH₄OH, 9:1:0.1).

D: Hydrogenation of Nitro to Amino:

0.2 mmol of the starting compound are dissolved in 20 ml of ethylacetate/methanol (1:1). Then the mixture is hydrogenated analogously toMethod C over Raney nickel. The residue is optionally chromatographed onsilica gel (dichloromethane/methanol/NH₄OH, 9:1:0.1).

TABLE IV (IB)

Melting point Example method R₂ R₆ R₇ chemical name (° C.) A phenyl Hamino (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-5- 220–223phenylsulphonylamino-2-indolinone A phenyl H piperazino-(Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl- 380 methylmethylidene]-5-phenylsulphonylamino-2-indolinone (decomp.) A 3-methoxy-H aminomethyl (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 200 phenylmethylidene]-5-(3-methoxyphenylsulphonylamino)-2- (decomp.)indolinone-hydrochloride A benzyl H aminomethyl(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 200methylidene]-5-benzylsulphonylamino)-2-indolinone- (decomp.)hydrochloride A 3-nitrophenyl H aminomethyl(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 215methylidene]-5-(3-nitrophenylsulphonylamino)-2- (decomp.)indolinone-hydrochloride A phenyl H ethylamino-(Z)-3-[1-(4-ethylaminomethyl-phenylamino)-1-phenyl- 230 methylmethylidene]-5-phenylsulphonylamino-2-indolinone- hydrotrifluoroacetateA phenyl H propylamino-(Z)-3-[1-(4-propylaminomethyl-phenylamino)-1-phenyl- 238 methylmethylidene]-5-phenylsulphonylamino-2-indolinone- hydrotrifluoroacetateA phenyl H butylamino-(Z)-3-[1-(4-butylaminomethyl-phenylamino)-1-phenyl- 260 methylmethylidene]-5-phenylsulphonylamino-2-indolinone- hydrotrifluoroacetateB phenyl H N-(2- (Z)-3-{1-[4-(N-(2-methylamino-ethyl)-N-acetyl-amino)-180 methylamino- phenylamino]-1-phenyl-methylidene}-5- (decomp.)ethyl)-N- phenylsulphonylamino-2-indolinone acetyl-amino B phenyl HN-(2- (Z)-3-{1-[4-(N-(2-methylamino-ethyl)-N-propionyl- 214 methylamino-amino)-phenylamino]-1-phenyl-methylidene}-5- ethyl)-N-phenylsulphonylamino-2-indolinone propionyl- amino C 3- Hpiperidinomethyl (Z)-3-[1-(4-piperidinomethyl-phenylamino]-1-phenyl- 237aminomethyl methylidene]-5-(3-aminomethyl-phenylsulphonylamino)-2-phenyl indolinone C phenyl H aminomethyl(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 230–232methylidene]-5-phenylsulphonylamino-2-indolinone C 2- H piperidinomethyl(Z)-3-[1-(4-piperidinomethyl-phenylamino]-1-phenyl- 237 aminomethylmethylidene]-5-(2-aminomethyl-phenylsulphonylamino)-2- phenyl indolinoneC 3- H N-methyl-N- (Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-277–279 aminomethyl acetyl-aminophenyl-methylidene}-5-(3-aminomethyl-phenylsulphonyl- phenylamino)-2-indolinone C 3- H pyrrolidin-1-(Z)-3-[1-(4-pyrrolidin-1-ylmethyl-phenylamino]-1-phenyl- 261 aminomethylylmethyl methylidene]-5-(3-aminomethyl-phenylsulphonylamino)-2- phenylindolinone D 4- H piperidinomethyl(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl- 279 aminophenylmethylidene]-5-(4-aminophenylsulphonylamino)-2- indolinone D 3- Hpiperidinomethyl (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl- 240aminophenyl methylidene]-5-(3-aminophenylsulphonylamino)-2- indolinone D2- H piperidinomethyl(Z)-3-[1-(4-piperidinomethyl-phenylamino]-1-phenyl- 220 aminophenylmethylidene]-5-(2-aminophenylsulphonylamino)-2- (decomp.)indolinone-hydrochloride D 3- H dimethylamino(Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl- 250 aminophenylmethyl methylidene]-5-(3-aminophenylsulphonylamino)-2- (decomp.)indolinone D 3- H N-methyl-N-(Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1- 207–209aminophenyl acetyl-aminophenyl-methylidene}-5-(3-aminophenylsulphonylamino)-2- indolinone D 2- HN-methyl-N- (Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-295–298 aminophenyl acetyl-aminophenyl-methylidene}-5-(2-aminophenylsulphonylamino)-2- indolinone D 3- Hpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino)-1- 242aminophenyl ylmethylphenyl-methylidene}-5-(3-aminophenylsulphonylamino)-2- indolinone D 3- H(2,6- (Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)- 150 aminophenyldimethylpiperidino)-phenylamino]-1-phenyl-methylidene}-5-(3-aminophenyl- (decomp.) methylsulphonylamino)-2-indolinone D 3- H aminomethyl(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 257 aminophenylmethylidene]-5-(3-aminophenylsulphonylamino)-2- indolinone D 3- H 4-(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1- 217–218aminophenyl methylpiperazino-phenyl-methylidene}-5-(3-aminophenylsulphonylamino)-2- methyl indolinoneD 2- H pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-l-ylmethyl)-phenylamino)-1-260 aminophenyl ylmethylphenyl-methylidene}-5-(2-aminophenylsulphonylamino)-2- indolinone Ex. 1methyl H acetylamino (Z)-3-{1-[4-acetylamino-phenylamino)-1-phenyl-299–303 methylidene}-5-methylsulphonylamino-2-indolinone Ex. 1 ethyl H2- (Z)-3-{1-[4-(2-dimethylamino-acetylamino)-phenylamino]- 238–241dimethylamino- 1-phenyl-methylidene}-5-ethylsulphonylamino-2-acetylamino indolinone Ex. 1 methyl H dimethylamino(Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1-phenyl- 240–242 methylmethylidene}-5-methylsulphonylamino-2-indolinone Ex. 1 n-propyl Hdimethylamino (Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1-phenyl-221–223 methyl methylidene}-5-n-propylsulphonylamino-2-indolinone Ex. 1n-butyl H dimethylamino-(Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1-phenyl- 210–213 methylmethylidene}-5-n-butylsulphonylamino-2-indolinone Ex. 1 ethyl Hdiethylamino- (Z)-3-{1-[4-diethylaminomethyl-phenylamino]-1-phenyl-182–185 methyl methylidene}-5-ethylsulphonylamino-2-indolinone Ex. 1ethyl H N-(2-dimethyl- (Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N- 201–203aminoethyl)-N- methylaminocarbonyl)-phenylamino]-1-phenyl- methylamino-methylidene}-5-ethylsulphonylamino-2-indolinone carbonyl Ex. 210 ethylCH₃ dimethylamino-(Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl- methylmethylidene]-5-(N-ethyl-N-phenylsulphonyl-amino)-2- indolinone Ex. 1pyrid-2-yl H (S)-2-hydroxy-(Z)-3-{1-[4-((S)-2-hydroxymethylpyrrolid-1-ylmethyl)- sintering methyl-phenylamino]-1-phenyl-methylidene}-5-pyrid-2- from 100 pyrrolidin-1-ylsulphonylamino-2-indolinone ylmethyl Ex. 1 pyrid-2-yl H (S)-3-hydroxy-(Z)-3-{1-[4-((S)-3-hydroxypyrrolid-1-ylmethyl)- sintering pyrrolidin-1-phenylamino]-1-phenyl-methylidene}-5-pyrid-2- from 130 ylmethylylsulphonylamino-2-indolinone

EXAMPLE 207(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene}-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinonea.(Z)-1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

10 g (20 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone(Example 1e) are dissolved in 150 ml of DMSO and combined with 2.2 g (20mmol) of potassium tert. butoxide with stirring. After 15 minutes'stirring 1.9 ml (31 mmol) of iodomethane are added. The mixture isstirred for 3 hours at ambient temperature. Then another 2.2 g (20 mmol)of potassium tert. butoxide and 1 ml (16 mmol) of iodomethane are added.The mixture is stirred for 18 hours at ambient temperature. Then wateris added. The reaction mixture is extracted with ethyl acetate. Theorganic phase is washed with water, dried over magnesium sulphate andevaporated to dryness. The residue is chromatographed on silica gel(petroleum ether/dichloromethane, 7:3).

Yield: 2.7 g (28% of theory)

R_(f) value: 0.65 (silica gel; dichloromethane/petroleum ether=8:2)

C₂₆H₂₄N₂O₅S (476.56)

Mass spectrum: (M+Na)⁺=499

b.(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene}-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

Prepared analogously to Example 1f from 350 mg (0.73 mmol) of(Z)-1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinoneand 257 mg (1 mmol) of4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline in DMF andsubsequent treatment with sodium hydroxide solution.

Yield: 380 mg (80% of theory)

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/NH₄OH=9:1:0.1)

C₃₃H₃₅N₅O₅S₂ (645.80)

Mass spectrum: M⁺=645

Calc.: C 61.38 H 5.46 N 10.84 Found: C 61.09 H 5.45 N 10.82

The following compounds of Examples 208 to 210 are prepared analogouslyto Example 207 using the intermediate products prepared in Examples I toXIII:

EXAMPLE 208(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-phenylamino)-1-phenyl-methylidene}-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

Melting point: 217° C.

R_(f) value: 0.5 (silica gel; dichloromethane/methanol/NH₄OH=9:1:0.1)

C₃₄H₃₅N₅O₄S (609.75)

Mass spectrum: (M+H)⁺=610

Calc.: C 66.97 H 5.79 N 11.49 Found: C 66.92 H 5.78 N 11.39

EXAMPLE 209(Z)-3-{1-[4-(N-methyl-N-piperidinomethylcarbonyl-amino)-phenylamino)-1-phenyl-methylidene}-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

Melting point: 160° C.

R_(f) value: 0.65 (silica gel; dichloromethane/methanol/NH₄OH=9:1:0.1)

C₃₆H₃₇N₅O₄S (635.79)

Mass spectrum: (M+H)⁺=636

EXAMPLE 210(Z)-3-[1-(3-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

Melting point: 226° C.

R_(f) value: 0.75 (silica gel; dichloromethane/methanol/NH₄OH=9:1:0.1)

C₃₁H₃₀N₄O₃S (538.67)

Mass spectrum: (M+H)⁺=539

The following compounds may be obtained analogously to the foregoingExamples:

-   (1)    (Z)-3-[1-(3-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone,    melting point 222–224° C.-   (2)    (Z)-3-{1-[4-(2-dimethylaminoethyl)-phenylamino]-1-phenyl-methylidene}-5-methylsulphonylamino-2-indolinone-   (3)    (Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone-   (4)    (Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone-   (5)    (Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone-   (6)    (Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-methylsulphonylamino-2-indolinone-   (7)    (Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone-   (8)    (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-methylsulphonylamino-2-indolinone-   (9)    (Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone-   (10)    (Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-methylsulphonylamino-2-indolinone-   (11)    (Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone-   (12)    (Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone-   (13)    (Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone-   (14)    (Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone-   (15)    (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone-   (16)    (Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone-   (17)    (Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone-   (18)    (Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone-   (19)    (Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-propylsulphonylamino-2-indolinone-   (20)    (Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone-   (21)    (Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone-   (22)    (Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone-   (23)    (Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-propylsulphonylamino-2-indolinone-   (24)    (Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone-   (25)    (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-propylsulphonylamino-2-indolinone-   (26)    (Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone-   (27)    (Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone-   (28)    (Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone-   (29)    (Z)-3-{1-[4-(2-dimethylaminoethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone-   (30)    (Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone-   (31)    (Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone-   (32)    (Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone-   (33)    (Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone-   (34)    (Z)-3-[1-(4-morpholinomethyl-phenylamino]-1-phenyl-methylidene)-5-cyclopropylsulphonylamino-2-indolinone-   (35)    (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone-   (36)    (Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone-   (37)    (Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone-   (38)    (Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone-   (39)    (Z)-3-{1-[4-(2-dimethylaminoethyl)-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone-   (40)    (Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone-   (41)    (Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone-   (42)    (Z)-3-{1-[4-(pyrrolidin-1-yl)-methyl-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone-   (43)    (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone-   (44)    (Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone-   (45)    (Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone-   (46)    (Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone-   (47)    (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone-   (48)    (Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone-   (49)    (Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-isopropylsulphonylamino-2-indolinone-   (50)    (Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone-   (51)    (Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone-   (52)    (Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone-   (53)    (Z)-3-{1-[4-(pyrrolidin-1-yl)-methyl-phenylamino]-1-phenyl-methylidene}-5-isopropylsulphonylamino-2-indolinone-   (54)    (Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone-   (55)    (Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-isopropylsulphonylamino-2-indolinone-   (56)    (Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone-   (57)    (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-isopropylsulphonylamino-2-indolinone

EXAMPLE 211

Dry ampoule containing 75 mg of active substance per 10 ml

Composition:

Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0mlPreparation:

Active substance and mannitol are dissolved in water. After packagingthe solution is freeze-dried. To produce the solution ready for use, theproduct is dissolved in water for injections.

EXAMPLE 212

Dry ampoule containing 35 mg of active substance per 2 ml

Composition:

Active substance  35.0 mg Mannitol 100.0 mg water for injections ad  2.0mlPreparation:

Active substance and mannitol are dissolved in water. After packaging,the solution is freeze-dried.

To produce the solution ready for use, the product is dissolved in waterfor injections.

EXAMPLE 213

Tablet containing 50 mg of active substance

Composition:

(1) Active substance  50.0 mg (2) Lactose  98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone  15.0 mg (5) Magnesium stearate  2.0mg 215.0 mgPreparation:

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side.

Diameter of the tablets: 9 mm.

EXAMPLE 214

Tablet containing 350 mg of active substance

Preparation:

(1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone  30.0 mg (5) Magnesium stearate  4.0mg 600.0 mg

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side.

Diameter of the tablets: 12 mm.

EXAMPLE 215

Capsules containing 50 mg of active substance

Composition:

(1) Active substance  50.0 mg (2) Dried maize starch  58.0 mg (3)Powdered lactose  50.0 mg (4) Magnesium stearate  2.0 mg 160.0 mgPreparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 3 hard gelatine capsules in acapsule filling machine.

EXAMPLE 216

Capsules containing 350 mg of active substance

Composition:

(1) Active substance 350.0 mg (2) Dried maize starch  46.0 mg (3)Powdered lactose  30.0 mg (4) Magnesium stearate  4.0 mg 430.0 mgPreparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 0 hard gelatine capsules in acapsule filling machine.

EXAMPLE 217

Suppositories containing 100 mg of active substance

1 suppository contains: active substance   100.0 mg polyethyleneglycol(M.W. 1500)   600.0 mg polyethyleneglycol (M.W. 6000)   460.0 mgpolyethylenesorbitan monostearate   840.0 mg 2,000.0 mgPreparation:

The polyethyleneglycol is melted together with polyethylene sorbitanmonostearate. At 40° C. the ground active substance is homogeneouslydispersed in the melt. It is cooled to 38° C. and poured into slightlychilled suppository moulds.

1. A compound of the formula I

or a pharmaceutically acceptable salt thereof, wherein: X is an oxygenor sulphur atom, R₁ is a hydrogen atom, a C₁₋₄-alkoxycarbonyl orC₂₋₄-alkanoyl group, R₂ is a pyridinyl group; R₃ is a hydrogen atom or aC₁₋₆-alkyl group, a phenyl group optionally substituted by a fluorine,chlorine or bromine atom, by a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy,C₁₋₃-alkylsulphenyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, nitro, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₂₋₅-alkanoylamino orN—(C₁₋₃-alkylamino)-C₂₋₅-alkanoylamino group, R4 is a phenyl or naphthylgroup substituted by R₇, which may additionally be substituted by achlorine or bromine atom or a nitro group, R₅ and R₆ in each caseindependently of one another are hydrogen atoms or C₁₋₃-alkyl groups,and R₇ is a a C₁₋₃-alkyl group which is substituted by a piperidinogroup, while the abovementioned piperidino group may be substituted byone or two C₁₋₃-alkyl groups, which may in turn be terminallysubstituted by a hydroxy, amino or C₂₋₄-alkanoylamino group, or by aC₅₋₇-cycloalkyl or phenyl group and by a hydroxy group and in theabovementioned piperidino group a methylene group adjacent to thenitrogen atom may be replaced by a carbonyl group.
 2. A compound offormula I according to claim 1 wherein the sulfonylamino group of theformula R₂—SO₂NR₆— is linked to the 5-position of the indolinone group.3. A compound of formula I according to claim 1, wherein: R₃ is a phenylgroup optionally substituted by a fluorine, chlorine or bromine atom, bya C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy, C₁₋₃-alkylsulphenyl,C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl, phenylsulphenyl,phenylsulphinyl, phenylsulphonyl, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃alkyl)-amino, C₂₋₅-alkanoylamino orN—(C₁₋₃-alkylamino)-C₂₋₅-alkanoylamino group.
 4. A compound of formula Iaccording to claim 1, wherein: X is an oxygen atom, R₁ is a hydrogenatom, R₂ is a pyridinyl group, R₃ is a hydrogen atom or a C₁₋₄-alkylgroup, or a phenyl group optionally substituted by a fluorine, chlorine,bromine or iodine atom, by a C₁₋₃alkyl, C₁₋₃-alkoxy, nitro or aminogroup, R₄ is a phenyl group substituted by R₇, R₅ and R₆ in each casedenote a hydrogen atom, and R₇ is a a C₁₋₃-alkyl group which issubstituted by a piperidino group, while the abovementioned piperidinogroup may be substituted by one or two C₁₋₃-alkyl groups, which may inturn be terminally substituted by a hydroxy, amino or C₂₋₄-alkanoylaminogroup, and at the same time in the abovementioned piperidino group amethylene group in the 2 position may be replaced by a carbonyl group.5. A compound of formula I according to claim 1, wherein: R₂ is apyridinyl group, R₃ is a phenyl group optionally substituted by afluorine, chlorine, bromine or iodine atom, by a C₁₋₃-alkyl,C₁₋₃-alkoxy, nitro or amino group, R₄ is a phenyl group which issubstituted by R₇ and additionally by a chlorine atom or a nitro group,while R₇ is a methyl or ethyl group which is substituted by a piperidinogroup.
 6. A compound of formula I according to claim 1, wherein R₄ is aphenyl group substituted in the 4 position by R₇.
 7. A compound offormula IB

wherein R₂ and R₇ are defined as in claim 1, 4 or
 5. 8. A compound offormula IB according to claim 7 wherein: R₇ is selected from the groupconsisting of: (2,6-dimethylpiperidino)-methyl and2-oxopiperidinomethyl; and R₂ is pyrid-2-yl or pyrid-3-yl. 9.(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone,or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalpreparation comprising a compound according to claim 1, 2, 3, 4, 5, 6,or 9 and a pharmaceutically acceptable carrier.